Inhibitors of c-fms kinase

ABSTRACT

The invention is directed to compounds of Formula I:  
                 
 
wherein A, X, R 2  and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget&#39;s disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

RELATIONSHIP TO OTHER APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 11/254,276filed Oct. 20, 2005 now ______; which in turn claimed benefit under 35U.S.C. § 119(e) to Provisional Applications No. 60/670,172, filed Apr.11, 2005 and Ser. No. 60/621,211, filed Oct. 22, 2004.

BACKGROUND OF THE INVENTION

The invention relates to novel compounds that function as proteintyrosine kinase inhibitors. More particularly, the invention relates tonovel compounds that function as inhibitors of c-fms kinase.

Protein kinases are enzymes that serve as key components of signaltransduction pathways by catalyzing the transfer of the terminalphosphate from adenosine 5′-triphosphate (ATP) to the hydroxy group oftyrosine, serine and threonine residues of proteins. As a consequence,protein kinase inhibitors and substrates are valuable tools forassessing the physiological consequences of protein kinase activation.The overexpression or inappropriate expression of normal or mutantprotein kinases in mammals has been demonstrated to play significantroles in the development of many diseases, including cancer anddiabetes.

Protein kinases can be divided into two classes: those whichpreferentially phosphorylate tyrosine residues (protein tyrosinekinases) and those which preferentially phosphorylate serine and/orthreonine residues (protein serine/threonine kinases). Protein tyrosinekinases perform diverse functions ranging from stimulation of cellgrowth and differentiation to arrest of cell proliferation. They can beclassified as either receptor protein tyrosine kinases or intracellularprotein tyrosine kinases. The receptor protein tyrosine kinases, whichpossess an extracellular ligand binding domain and an intracellularcatalytic domain with intrinsic tyrosine kinase activity, aredistributed among 20 subfamilies.

Receptor tyrosine kinases of the epidermal growth factor (“EGF”) family,which includes HER-1, HER-2/neu and HER-3 receptors, contain anextracellular binding domain, a transmembrane domain and anintracellular cytoplasmic catalytic domain. Receptor binding leads tothe initiation of multiple intracellular tyrosine kinase dependentphosphorylation processes, which ultimately results in oncogenetranscription. Breast, colorectal and prostate cancers have been linkedto this family of receptors.

Insulin receptor (“IR”) and insulin-like growth factor I receptor(“IGF-1R”) are structurally and functionally related but exert distinctbiological effects. IGF-1R over-expression has been associated withbreast cancer.

Platelet derived growth factor (“PDGF”) receptors mediate cellularresponses that include proliferation, migration and survival and includePDGFR, the stem cell factor receptor (c-kit) and c-fms. These receptorshave been linked to diseases such as atherosclerosis, fibrosis andproliferative vitreoretinopathy.

Fibroblast growth factor (“FGR”) receptors consist of four receptorswhich are responsible for the production of blood vessels, for limboutgrowth, and for the growth and differentiation of numerous celltypes.

Vascular endothelial growth factor (“VEGF”), a potent mitogen ofendothelial cells, is produced in elevated amounts by many tumors,including ovarian carcinomas. The known receptors for VEGF aredesignated as VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4). A relatedgroup of receptors, tie-1 and tie-2 kinases, have been identified invascular endothelium and hematopoietic cells. VEGF receptors have beenlinked to vasculogenesis and angiogenesis.

Intracellular protein tyrosine kinases are also known as non-receptorprotein tyrosine kinases. Over 24 such kinases have been identified andhave been classified into 11 subfamilies. The serine/threonine proteinkinases, like the cellular protein tyrosine kinases, are predominantlyintracellular.

Diabetes, angiogenesis, psoriasis, restenosis, ocular diseases,schizophrenia, rheumatoid arthritis, cardiovascular disease and cancerare exemplary of pathogenic conditions that have been linked withabnormal protein tyrosine kinase activity. Thus, a need exists forselective and potent small-molecule protein tyrosine kinase inhibitors.U.S. Pat. Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and PCTInternational Applications WO 01/47897, WO 00/27820 and WO 02/068406 areindicative of recent attempts to synthesize such inhibitors.

SUMMARY OF THE INVENTION

The invention addresses the current need for selective and potentprotein tyrosine kinase inhibitors by providing potent inhibitors ofc-fms kinase. The invention is directed to the novel compounds ofFormula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:A is

phenyl or pyridyl, either of which may be substituted with one ofchloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl),—O(alkyl), or 4-aminophenyl;

W is

pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl(including furan-2-yl), any of which may be connected through any carbonatom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4triazolyl, or furanyl may contain one —Cl, —CN, —NO₂, —OMe, or —CF₃substitution, connected to any other carbon;

R² is

cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl,dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, ordihydropyranyl, any of which may be independently substituted with oneor two of each of the following: chloro, fluoro, and C₍₁₋₃₎alkyl(including 4,4-dimethyl cyclohexenyl, 4-methyl cyclohexenyl, 2-methylthiophenyl, 3-methyl thiophenyl), with the proviso thattetrahydropyridyl is connected to the ring A through a carbon-carbonbond;X is

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;

R_(a) and R_(b) are independently

-   -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including        1-hydroxyeth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from S, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;

R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

The compounds of Formula I are especially potent inhibitors of the c-fmsprotein tyrosine kinase.

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to the novel compounds of Formula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:

A is

-   -   phenyl or pyridyl, either of which may be substituted with one        of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂,        —S(alkyl), —O(alkyl), or 4-aminophenyl;

W is

-   -   pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including        1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the pyrrolyl, imidazolyl,        isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain        one —Cl, —CN, —NO₂, —OMe, or —CF₃ substitution, connected to any        other carbon;

R² is

-   -   cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl,        dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or        dihydropyranyl, any of which may be independently substituted        with one or two of each of the following: chloro, fluoro, and        C₍₁₋₃₎alkyl (including 4,4-dimethyl cyclohexenyl, 4-methyl        cyclohexenyl, 2-methyl thiophenyl, 3-methyl thiophenyl), with        the proviso that tetrahydropyridyl is connected to the ring A        through a carbon-carbon bond;

X is

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;

R_(a) and R_(b) are independently

hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including 1-hydroxy        eth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from S, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;

R⁴is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

Embodiments of the present invention include a compound of Formula Iwherein:

a) A is

-   -   phenyl or pyridyl, either of which may be substituted with one        of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂,        —S(alkyl), —O(alkyl), or 4-aminophenyl;

b) A is

-   -   phenyl;

c) W is

-   -   pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including        1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the pyrrolyl, imidazolyl,        isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain        one —Cl, —CN, —NO₂, —OMe, or —CF₃ substitution, connected to any        other carbon;

d) W is

-   -   furan-2-yl, 1H-pyrrol-2-yl, or 1H-imidazol-2-yl, any of which        may be substituted at the 4 or 5 carbons with —CN;

e) W is

-   -   3H-2-imidazolyl-4-carbonitrile or 5-cyano-1H-pyrrol-2-yl;

f) W is

-   -   3H-2-imidazolyl-4-carbonitrile;

g) R² is

-   -   cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl,        dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or        dihydropyranyl, any of which may be independently substituted        with one or two of each of the following: chloro, fluoro, and        C₍₁₋₃₎alkyl (including 4,4-dimethyl cyclohexenyl, 4-methyl        cyclohexenyl, 2-methyl thiophenyl, 3-methyl thiophenyl), with        the proviso that tetrahydropyridyl is connected to the ring A        through a carbon-carbon bond;

h) R² is

-   -   cycloalkyl (including cyclohexenyl, cyclopentenyl), which may        substituted with one or two C₍₁₋₃₎alkyl (including 4,4-dimethyl        cyclohexenyl, 4-methyl cyclohexenyl);

i) R² is

-   -   cyclohexenyl, which may substituted with one or two C₍₁₋₃₎alkyl:

j) R² is

-   -   cyclohexenyl, 4,4-dimethyl cyclohexenyl, or 4-methyl        cyclohexenyl;

k) R² is

-   -   cyclohexenyl;

l) X is

m) X is

n) X is

o) Z is

-   -   CH or N;

p) Z is

-   -   CH;

q) D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

r) D¹ and D² are

-   -   each hydrogen;

s) D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

t) D³ and D⁴ are

-   -   each hydrogen;

u) D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;

v) R_(a) and R_(b) are independently

-   -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

w) E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

x) E is N, with the proviso that E may not be N if the following threeconditions are simultaneously met: Q_(a) is absent, Q_(b) is absent, andR³is an amino group or cyclic amino radical wherein the point ofattachment to E is N;

y) Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

z) Q_(a) is

-   -   absent, —CH₂CH₂—, or C(O);

aa) Q_(a) is

-   -   absent, or C(O);

bb) Q_(a) is

-   -   C(O);

cc) Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

dd) Q_(b) is

-   -   absent, —CH₂CH₂—, or C(O), with the proviso that Q_(b) may not        be C(O) if Q_(a) is C(O);

ee) Q_(b) is

-   -   absent, or C(O), with the proviso that Q_(b) may not be C(O) if        Q_(a) is C(O);

ff) R³ is

-   -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including 1-hydroxy        eth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from S, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;

gg) R³ is

-   -   hydrogen, phenyl, 2-hydroxy ethylamino,        1-hydroxyeth-2-yl(methyl)amino, methylamino, 2-amino isopropyl,        1,3-dihydroxy isopropyl, 1,2-dihydroxy ethyl, methoxy,        dimethylamino, 1-hydroxy eth-2-yl, —COOH, —CONH₂, —CN, —SO₂—,        —SO₂CH₃), —NH₂, piperidinyl, morpholinyl, imidazolyl, pyridyl,        pyridyl N-oxide), or 1 methyl imidazolyl;

hh) R³ is

-   -   alkylamino (including methylamino), dialkylamino (including        dimethylamino), or —SO₂-alkyl-R⁴ (including —SO₂CH₃);

ii) R³ is

-   -   methylamino, dimethylamino, or —SO₂CH₃;

jj) R³ is

-   -   dimethylamino;

kk) R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl; and

ll) R⁴ is

-   -   hydrogen;

and all combinations of a) to ll), inclusive, herein above.

Preferred compounds of Formula I are those wherein

W is substituted with one —CN.

Other preferred compounds of Formula I are those wherein:

A is

-   -   pyridyl, which may be substituted with one of chloro, fluoro,        methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl),        or 4-aminophenyl;

W is

-   -   imidazolyl, (including 1H-imidazol-2-yl), which may contain one        —CN; and

R² is

-   -   cycloalkyl.

Still other preferred compounds of Formula I are those wherein:

A is

-   -   phenyl which may be substituted with one of chloro, fluoro, or        methyl;

X is

and is attached to the phenyl A ring para to the nitrogen substituent,as depicted in formula II;

D³ and D⁴ are hydrogen;

E is

-   -   N or SO₂, with the proviso that E may not be N if the following        three conditions are simultaneously met: Q_(a) is absent, Q_(b)        is absent, and R³is an amino group or cyclic amino radical        wherein the point of attachment to E is N; and

R³ is

-   -   hydrogen, piperidinyl, alkylamino, dialkylamino,        hydroxyalkylamino, (hydroxyalkyl)₂amino, imidazolyl, 1-methyl        imidazolyl, pyridyl, pyridyl N-oxide, hydroxyalkyl, —COOH,        —CONH₂, —CN, —SO₂CH₃, —NH₂, morpholinyl; R³ may also be absent,        with the proviso that R³ is not absent when E is nitrogen.

More preferred compounds of Formula I are those wherein:

A is

-   -   phenyl;

W is

-   -   furan-2-yl, 1H-pyrrol-2-yl, or 1H-imidazol-2-yl, any of which        may be substituted at the 4 or 5 carbons with —CN;

R² is

-   -   cycloalkyl, dihydrosulfonopyranyl, phenyl, furanyl,        tetrahydropyridyl, or dihydropyranyl, any of which may be        independently substituted with one or two of each of the        substituents selected from the group consisting of chloro,        fluoro, and C₍₁₋₃₎alkyl, with the proviso that tetrahydropyridyl        must be connected to the ring A through a carbon-carbon bond.

Even more preferred compounds of Formula I are those wherein:

W is

-   -   3H-2-imidazolyl-4-carbonitrile or 5-cyano-1H-pyrrol-2-yl;

R² is

-   -   cyclohexenyl, or cyclopentenyl, either of which may be        substituted with chloro, fluoro or one two C₍₁₋₃₎alkyl groups;

E is

-   -   N, with the proviso that E may not be N if the following three        conditions are simultaneously met: Q_(a) is absent, Q_(b) is        absent, and R³ is an amino group or cyclic amino radical wherein        the point of attachment to E is N;

Z is CH.

Especially preferred compounds of Formula I are those wherein:

W is

imidazolyl, (including 1H-imidazol-2-yl), 1,2,4 triazolyl, or furanyl(including furan-2-yl), any of which may be connected through any carbonatom, wherein the imidazolyl, 1,2,4 triazolyl, or furanyl may containone —Cl or —CN, connected to any other carbon;

R² is

-   -   cycloalkyl (including C₍₁₋₃₎alkyl substituted cycloalkyl,        further including C₍₁₋₃₎alkyl substituted cyclopentenyl, and        C₍₁₋₃₎alkyl substituted cyclohexenyl, further including 4-methyl        cyclohexenyl), C₍₁₋₃₎dialkyl substituted cycloalkyl (including        4,4-dimethyl cyclohexenyl), thiophenyl (including C₍₁₋₃₎alkyl        substituted thiophenyl, further including 2-methyl thiophenyl        and 3-methyl thiophenyl), C₍₁₋₃₎alkyl substituted phenyl        (including methyl phenyl), dihydropyranyl, and        1,1-dioxo-tetrahydrothiopyranyl;

X is

E is

-   -   N or SO₂, with the proviso that E may not be N if the following        three conditions are simultaneously met: Q_(a) is absent, Q_(b)        is absent, and R³ is an amino group or cyclic amino radical        wherein the point of attachment to E is N; and

R³ is

-   -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), hydroxyalkyl(alkyl)amino (including        1-hydroxyeth-2-yl (methyl)amino), alkylamino (including        methylamino), aminoalkyl (including 2-amino isopropyl),        dihydroxyalkyl (including 1,3-dihydroxy isopropyl, 1,2-dihydroxy        ethyl), alkoxy (including methoxy), dialkylamino (including        dimethylamino), hydroxyalkyl (including 1-hydroxy eth-2-yl),        —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, or a 5 or six membered ring        selected from the group consisting of: piperidinyl, morpholinyl,        imidazolyl, and pyridyl, wherein the 5 or 6 membered ring may be        optionally substituted with methyl, halogen, alkylamino, or        alkoxy (including 1 methyl imidazolyl), R³ may also be absent,        with the proviso that R³ is not absent when E is nitrogen.

Most preferred compounds of Formula I are those wherein:

W is

-   -   3H-2-imidazolyl-4-carbonitrile;

Q_(a) is CO;

R³ is

-   -   hydrogen, piperidinyl, hydroxyalkylamino, (hydroxyalkyl)₂amino,        alkylamino, dialkylamino, imidazolyl, 1-methyl imidazolyl,        pyridyl, pyridyl N-oxide, hydroxyalkyl, —COOH, —CONH₂, —CN,        —SO₂CH₃, —NH₂, morpholinyl.

The compounds of Formula I are especially potent inhibitors of the c-fmsprotein tyrosine kinase.

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I.

Examples of compounds of Formula I are:

5-cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide,or

5-cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(2-methyl-thiophen-3-yl)-phenyl]-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

More preferred examples of compounds of Formula I are:

4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide,

5-cyano-furan-2-carboxylic acid[2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide,

5-cyano-furan-2-carboxylic acid[2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide,

5-cyano-furan-2-carboxylic acid[2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide, or

5-cyano-furan-2-carboxylic acid[2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

Even more preferred examples of compounds of Formula I are:

(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-aceticacid,

4-cyano-1H-imidazole-2-carboxylic acid[4-(1-carbamoylmethyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex- I-enyl-4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-cyano-ethyl)-piperidin-4-yl ]-2-cyclohex-1-enyl-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid(2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide,

4-cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide,

4-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-phenyl]-amide,or

4-cyano-1H-pyrrole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

Most preferred examples of compounds of Formula I are:

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-4-carbonyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-phenyl}-amide,

4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide,

4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-3H-imidazol-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-phenyl}-amide,

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,or

4-cyano-1H-imidazole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide.

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

Another most preferred compound of Formula I is:

4-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-{2-[(2-hydroxy-ethyl)-methyl-amino]-acetyl}-piperidin-4-yl)-phenyl]-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

An additional most preferred compound of Formula I is:

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

One more most preferred compound of Formula I is:

4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

Still other preferred compounds of formula I are:

4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt,

4H-[1,2,4]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroaceticacid salt,

5-Chloro-4H-[1,2,4]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt,

5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt,

5-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amidebis trifluoroacetic acid salt,

5-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide,

5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt,

4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt,

5-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt, and

5-Cyano-1H-imidazole-2-carboxylic acid[6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide,

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

Additional preferred compounds of Formula I are:

4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide,

4-Cyano-1H-imidazole-2-carboxylic acid[1′-(2-dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt,

4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt,

5-Cyano-1H-imidazole-2-carboxylic acid[4-(3,6-dihydro-2H-pyran-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide;

4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohept-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt;

4-Cyano-1H-imidazole-2-carboxylic acid[4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amidetrifluoroacetic acid salt;

4-Cyano-1H-pyrrole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt;

4-Cyano-1-imidazole-2-carboxylic acid{2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt;

and solvates, hydrates, tautomers and pharmaceutically acceptable saltsthereof.

The invention also relates to methods of inhibiting protein tyrosinekinase activity in a mammal by administration of a therapeuticallyeffective amount of at least one compound of Formula I. A preferredtyrosine kinase is c-fms.

The invention is considered to include the enantiomeric, diastereomericand tautomeric forms of all compounds of Formula I as well as theirracemic mixtures. In addition, some of the compounds represented byFormulae I may be prodrugs, i.e., derivatives of an acting drug thatpossess superior delivery capabilities and therapeutic value as comparedto the acting drug. Prodrugs are transformed into active drugs by invivo enzymatic or chemical processes.

I. Definitions

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwiseindicated, and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl.

The term “hydroxyalkyl” refers to both linear and branched chainradicals of up to 6 carbon atoms, in which one hydrogen atom has beenreplaced with an OH group.

The term “hydroxyalkylamino” refers to an hydroxyalkyl group in whichone hydrogen atom from the carbon chain has been replaced with an aminogroup, wherein the nitrogen is the point of attachment to the rest ofthe molecule.

The term “cycloalkyl” refers to a saturated or partially unsaturatedring composed of from 3 to 8 carbon atoms. Up to four alkyl substituentsmay optionally be present on the ring. Examples include cyclopropyl,1,1-dimethyl cyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl,cyclopentenyl, cyclohexenyl, and 4,4-dimethyl cyclohexenyl.

The term “dihydrosulfonopyranyl” refers to the following radical:

The term “hydroxyalkyl” refers to at least one hydroxyl group bonded toany carbon atom along an alkyl chain.

The term “aminoalkyl” refers to at least one primary or secondary aminogroup bonded to any carbon atom along an alkyl chain, wherein an alkylgroup is the point of attachment to the rest of the molecule.

The term “alkylamino” refers to an amino with one alkyl substituent,wherein the amino group is the point of attachment to the rest of themolecule.

The term “dialkylamino” refers to an amino with two alkyl substituents,wherein the amino group is the point of attachment to the rest of themolecule.

The term “heteroaromatic” or “heteroaryl” refers to 5- to 7-memberedmono- or 8- to 10-membered bicyclic aromatic ring systems, any ring ofwhich may consist of from one to four heteroatoms selected from N, O orS where the nitrogen and sulfur atoms can exist in any allowed oxidationstate. Examples include benzimidazolyl, benzothiazolyl, benzothienyl,benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl,thiazolyl and thienyl.

The term “heteroatom” refers to a nitrogen atom, an oxygen atom or asulfur atom wherein the nitrogen and sulfur atoms can exist in anyallowed oxidation states.

The term “alkoxy” refers to straight or branched chain radicals of up to12 carbon atoms, unless otherwise indicated, bonded to an oxygen atom.Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.

The term “aryl” refers to monocyclic or bicyclic aromatic ring systemscontaining from 6 to 12 carbons in the ring. Alkyl substituents mayoptionally be present on the ring. Examples include benzene, biphenyland napththalene.

The term “aralkyl” refers to a C₁₋₆ alkyl group containing an arylsubstituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.

The term “sulfonyl” refers to the group —S(O)₂R_(a), where R_(a) ishydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl. A “sulfonylating agent” adds the —S(O)₂R_(a) group to amolecule.

II. Therapeutic Uses

The compounds of Formula I represent novel potent inhibitors of proteintyrosine kinases, such as c-fms, and may be useful in the prevention andtreatment of disorders resulting from actions of these kinases.

The invention also provides methods of inhibiting a protein tyrosinekinase comprising contacting the protein tyrosine kinase with aneffective inhibitory amount of at least one of the compounds of FormulaI. A preferred tyrosine kinase is c-fms. The compounds of the presentinvention are also inhibitors of FLT3 tyrosine kinase activity. In oneembodiment of inhibiting a protein tyrosine kinase, at least one of thecompounds of Formula I is combined with a known tyrosine kinaseinhibitor.

In various embodiments of the invention, the protein tyrosine kinasesinhibited by the compounds of Formula I are located in cells, in amammal or in vitro. In the case of mammals, which includes humans, atherapeutically effective amount of a pharmaceutically acceptable formof at least one of the compounds of Formula I is administered.

The invention further provides methods of treating cancer in mammals,including humans, by administration of a therapeutically effectiveamount of a pharmaceutically acceptable composition of least onecompound of Formula I. Exemplary cancers include, but are not limitedto, acute myeloid leukemia, acute lymphocytic leukemia, ovarian cancer,uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cellleukemia and non-small lung carcinoma. The invention also providesmethods of treating certain precancerous lesions includingmyelofibrosis. In one embodiment of the invention, an effective amountof at least one compound of Formula I is administered in combinationwith an effective amount of a chemotherapeutic agent.

The invention further provides methods of treating and of preventingmetastasis arising from cancers that include, but are not limited to,ovarian cancer, uterine cancer, breast cancer, colon cancer, stomachcancer, hairy cell leukemia and non-small lung carcinoma.

The invention further provides methods for the treatment osteoporosis,Paget's disease, and other diseases in which bone resorption mediatesmorbidity including arthritis, prosthesis failure, osteolytic sarcoma,myeloma, and tumor metastasis to bone as occurs frequently in cancersincluding, but not limited to, breast cancer, prostate cancer, and coloncancer.

The invention also provides methods of treating pain, in particularskeletal pain caused by tumor metastasis or osteoarthritis, as well asvisceral, inflammatory, and neurogenic pain.

The invention also provides methods of treating cardiovascular,inflammatory, and autoimmune diseases in mammals, including humans, byadministration of a therapeutically effective amount of apharmaceutically acceptable form of at least one of the compounds ofFormula I. Examples of diseases with an inflammatory component includeglomerulonephritis, inflammatory bowel disease, prosthesis failure,sarcoidosis, congestive obstructive pulmonary disease, asthma,pancreatitis, HIV infection, psoriasis, diabetes, tumor relatedangiogenesis, age-related macular degeneration, diabetic retinopathy,restenosis, schizophrenia or Alzheimer's dementia. These may beeffectively treated with compounds of this invention. Other diseasesthat may be effectively treated include, but are not limited toatherosclerosis and cardiac hypertrophy. Autoimmune diseases such assystemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrom,multiple sclerosis, or uveitis, can also be treated with compounds ofthis invention.

When employed as protein tyrosine kinase inhibitors, the compounds ofthe invention may be administered in an effective amount within thedosage range of about 0.5 mg to about 10 g, preferably between about 0.5mg to about 5 g, in single or divided daily doses. The dosageadministered will be affected by factors such as the route ofadministration, the health, weight and age of the recipient, thefrequency of the treatment and the presence of concurrent and unrelatedtreatments.

The compounds of Formula I may be formulated into pharmaceuticalcompositions comprising any known pharmaceutically acceptable carriers.Exemplary carriers include, but are not limited to, any suitablesolvents, dispersion media, coatings, antibacterial and antifungalagents and isotonic agents. Exemplary excipients that may also becomponents of the formulation include fillers, binders, disintegratingagents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts which are formed from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, benzoate,benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride,hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate,pivalate, propionate, succinate, sulfate and tartrate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamino salts and salts withamino acids such as arginine. Also, the basic nitrogen-containing groupsmay be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered byany means that accomplish their intended purpose. Examples includeadministration by parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, buccal or ocular routes. Alternatively orconcurrently, administration may be by the oral route. Suitableformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form, for example, water-solublesalts, acidic solutions, alkaline solutions, dextrose-water solutions,isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, the compounds mayform solvates, for example with water (i.e., hydrates) or common organicsolvents. As used herein, the term “solvate” means a physicalassociation of the compounds of the present invention with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scopesolvates of the compounds of the present invention. Thus, in the methodsof treatment of the present invention, the term “administering” shallencompass the means for treating, ameliorating or preventing a syndrome,disorder or disease described herein with the compounds of the presentinvention or a solvate thereof, which would obviously be included withinthe scope of the invention albeit not specifically disclosed.III. Methods of Preparation

Scheme I illustrates general methodology for the preparation ofcompounds of Formula I.

Compounds of Formula 1-2 can be obtained by ortho-halogenation,preferably bromination, of amino compounds of Formula 1-1 followed bymetal-catalyzed coupling reactions with boronic acids or boronate esters(Suzuki reactions, where R²M is R²B(OH)₂ or a boronic ester) or tinreagents (Stille reactions, where R²M is R²Sn(alkyl)₃) (for reviews, seeN. Miyaura, A. Suzuki, Chem. Rev., 95:2457 (1995), J. K. Stille, Angew.Chem, Int. Ed. Engl., 25: 508024 (1986) and A. Suzuki in Metal-CatalyzedCoupling Reactions, F. Deiderich, P. Stang, Eds., Wiley-VCH, Weinheim(1988)). Compounds of formula 1-1 may be commercially available, or theabove palladium mediated cross-coupling reactions described above may beused to generate compounds of Formula 1-1 from starting material 1-0.

Preferred conditions for the bromination of 1-1 are N-bromosuccinimide(NBS) in a suitable solvent such as N,N-dimethylformamide (DMF),dichloromethane (DCM) or acetonitrile. Metal-catalyzed couplings,preferably Suzuki reactions, can be performed according to standardmethodology, preferably in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), an aqueous basesuch aq. Na₂CO₃, and a suitable solvent such as toluene, ethanol,dimethoxyethane (DME), or DMF.

Compounds of Formula I can be prepared by reaction of compounds ofFormula 1-2 with carboxylic acids WCOOH according to standard proceduresfor amide bond formation (for a review, see: M. Bodansky and A.Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY (1984))or by reaction with acid chlorides WCOCl or activated esters WCO₂Rq(where Rq is a leaving group such as pentafluorophenyl orN-succinimide). The preferred reaction conditions for coupling withWCOOH are: when W is a furan, oxalyl chloride in DCM with DMF as acatalyst to form the acid chloride WCOCl and then coupling in thepresence of a trialkylamine such as DIEA; when W is a pyrrole,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and1-hydroxybenzotriazole-6-sulfonamidomethyl hydrochloride (HOBt); andwhen W is an imidazole, the preferred conditions arebromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) anddiisopropylethylamine (DIEA) in DCM.

It is understood that the optional substitution present on ring A inFormula I may be present in the starting materials 1-1 or 1-3 and, insuch cases, would be carried through the synthesis outlined in Scheme 1.Alternatively various substituents on compounds of Formula I may beintroduced in a number of ways described below to provide the optionalsubstitution listed for Formula I. The leaving group “L₁” present onring A in Formula 1-0 or 1-3, can be substituted before or at any stepduring Scheme 1. When such leaving groups (preferably fluoro or chloro)are activated by the nitro group of Formula 1-3 for nucleophilic attack,they can undergo direct nucleophilic aromatic substitution by ammoniaand azide anion or by amines, alcohols, thiols and other nucleophiles inthe presence of a suitable base such as K₂CO₃, N,N-diisopropylethylamine(DIEA) or NEt₃. When the leaving group is suitable for metal-catalyzedcouplings (preferably bromo or trifluoromethanesulfonyloxy), a number ofcross-coupling reactions (such as Suzuki or Stille reactions asdiscussed above for the introduction of R²) may be performed. Othermetal-catalyzed coupling reactions that can be employed include aromaticand heteroaromatic amination and amidation (for reviews, see: S. L.Buchwald, et al, Top. Curr. Chem., 219:131-209 (2001) and J. F. Hartwigin “Organopalladium Chemistry for Organic Synthesis,” WileyInterscience, NY (2002). Additional metal catalyzed cross couplingreactions with 2,4,6-trimethyl-cyclotriboroxane may be employed if L₁ isbromo, iodo, or chloro activated by nitro to generate optional methylsubstitution (see M. Gray, et al, Tetrahedron Lett., 41: 6237-40 (2000))

In some cases, the initial substituents can be further derivatized asdescribed below to provide the final substitution of Formula I.

An alternative method for the introduction of nitrogen-containingheterocyclic substituents onto ring A is to form the heterocycle from anamino group on ring A. The amino group may be originally present in thestarting material in a protected or unprotected form or may result fromthe reduction of a nitro group which also can be either originallypresent in the starting material or attached by a nitration reaction. Inaddition, the amino group may be formed by reduction of an azide groupwhich can be present in the starting material or may result fromnucleophilic aromatic substitution of an activated halide by azide anionas mentioned above. The amino group may also result from nucleophilicaromatic substitution of an activated halide (in, for example anitrohalo compound) by ammonia or by the anion of a protected ammoniaequivalent, for example, t-butyl carbamate. If introduced in protectedform, the amine can be deprotected according to standard literaturemethods. (For examples of amine protecting groups and deprotectionmethods see: Theodora W. Greene and Peter G. M. Wuts, John Wiley andSons, Inc., NY (1991).) The ring-forming reaction involves treatment ofthe aniline amino group with a suitable optionally substituteddi-electrophile, preferably a dihalide or dicarbonyl compound, whichresults in two substitutions on the amino group to form an optionallysubstituted heterocycle. In the case of dihalides, any of a number ofsuitable bases can be added as an acid scavenger such as potassiumcarbonate, sodium hydroxide, or, a trialkylamine such as triethylamine.Thus, treatment with a bis(2-haloethyl)amine such asbis(2-chloroethyl)amine or bis(2-bromoethyl)amine would afford apiperazine ring (see, for example, J. Med. Chem., 29: 640-4 (1986) andJ. Med. Chem., 46: 2837 (2003)). Optional substitution on the aminenitrogen of the reagent would incorporate optional substitution on theterminal amine of the piperazine. For example, treatment withN,N-bis(2-chloroethyl)aniline would give an N-phenylpiperazino group.Treatment with a bis(2-haloethyl)ether or bis(2-haloethyl)thioetherwould afford a morpholine or thiomorpholine ring, respectively.

Another alternative method to direct substitution to introduceheterocyclic substituents onto ring A is to form the heterocycle from analdehyde (i.e. from a formyl group on ring A). The formyl group may beoriginally present in the starting material in a protected orunprotected form or may result from or any of a number of formylationreactions known in the literature including a Vilsmeier-Haack reaction(for a review of formylation chemistry, see: G. A. Olah, et al, ChemRev., 87: (1987)) or by para-formylation of nitroaromatics (see: A.Katritsky and L. Xie, Tetrahedron Lett., 37:347-50 (1996)).

Finally it is understood that compounds of Formula I may be furtherderivatized. Protecting groups on compounds of Formula I can be removedaccording to standard synthetic methodologies (Theodora W. Greene andPeter G. M. Wuts, John Wiley and Sons, Inc., NY (1991)) and can be thensubjected to further derivatization. Examples of further derivatizationof compounds of I include, but are not limited to: when compounds ofFormula I contain a primary or secondary amine, the amine may be reactedwith aldehydes or ketones in the presence of a reducing agent such assodium triacetoxyborohydride (see Abdel-Magid J. Org. Chem. 61, pp.3849-3862, (1996)) to reductively alkylate; with acid chlorides orcarboxylic acids and an amide bond forming reagent as described above toform amides; with sulfonyl chlorides to form sulfonamides; withisocyanates to form ureas; with aryl- or heteroaryl-halides in thepresence of a palladium catalyst as described above (see Buchwald andHartwig references above) to form aryl and heteroarylamines. Inaddition, when compounds of Formulae I contain an aryl halide orheteroaryl halide, these compounds may be subjected to metal-catalyzedreactions with boronic acids (for example, Suzuki or Stille couplings asdescribed above), or, amines or alcohols (Buchwald- or Hartwig-typecouplings, see Buchwald and Hartwig references above). When compounds ofFormulae I contain a cyano group, this group may be hydrolyzed to amidesor acids under acid or basic conditions. Basic amines may be oxidized toN-oxides and conversely N-oxides may be reduced to basic amines. Whencompounds of Formula I contain a sulfide, either acyclic or cyclic, thesulfide can be further oxidized to the corresponding sulfoxides orsulfones. Sulfoxides can be obtained by oxidation using an appropriateoxidant such as one equivalent of (meta-chloroperbenzoicacid) MCPBA orby treatment with NaIO₄ (see, for example, J. Regan, et al, J. Med.Chem., 46: 4676-86 (2003)) and sulfones can be obtained using twoequivalents of MCPBA or by treatment with 4-methylmorpholine N-oxide andcatalytic osmium tetroxide (see, for example, PCT application WO01/47919).

Scheme 2a illustrates a route to compounds of Formula I. F represents—NQ_(a)Q_(b)R³—, —O—, S, SO, or SO₂, and AA represents —NH₂ or —NO₂. D¹and D² are shown for illustrative purposes only; it is recognized bythose skilled in art that D⁵ D⁶ D⁷ D⁸ may also be present. Ketones offormula 2-1 can be converted to a vinyl triflate of formula 2-2 bytreatment with a non-nucleophilic base such as LDA and then trapping ofthe resulting enolate with a triflating reagent such astrifluoromethanesulfonic anhydride or preferablyN-phenyltrifluoromethanesulfonimide. Suzuki coupling of boronic acids orboronate esters of formula 2-3 to vinyl triflates of formula 2-2 canprovide compounds of formula 2-4 where Z=C (Synthesis, 993 (1991)).

For compounds of formula 2-4 treatment with Pd/C can reduce both theolefin (and the nitro if AA=NO₂) to give Z=CH, AA=NH₂. Compounds offormula 2-4 where F represents —SO₂ can be prepared from compounds offormula 2-4 where AA=—NO₂ and F is a sulfide (F=—S—) by oxidation withMCPBA or other methods described in Scheme 1. The nitro group may thenbe reduced with Pd/C to reduce both the nitro and the olefin.

Compounds of formula 2-4 (AA=NH₂) are then converted to compounds ofFormula 2-5 (which also represent compounds of Formulae I if no furthermodifications are required) as described in Scheme 1.

Compounds of formula 2-5 may be further modified to provide additionalcompounds of Formula I. For example, in cases where F is—NQ_(a)Q_(b)R³—, Q_(a)Q_(b)=a direct bond, and R₃ represents a BOCprotecting group (CO₂tBu), the BOC group may be removed according tostandard methodology such as trifluoroactic acid (TFA) in DCM (Greeneand Wuts, ibid.) to provide a secondary amine that can then be furtherderivatized to provide compounds of Formula I. Further derivatizationincludes, but is not limited to: reactions with aldehydes or ketones inthe presence of a reducing agent such as sodium triacetoxyborohydride toprovide compounds of Formula II where F=—NCH₂R³ (A. F. Abdel-Magid,ibid.); with acid chlorides or with carboxylic acids and an amide bondforming reagent (as described in Scheme 1) to provide compounds offormula II where F=—NCOR³; with sulfonyl chlorides (as described inScheme 1) to provide compounds of Formula I where F=—NSO₂R_(a); withisocyanates(as described in Scheme 1) to provide compounds of Formula IIwhere F=—NCONR_(a)R_(b); or subjected to metal-catalyzed substitutionreactions as outlined in Scheme I to provide compounds of Formula Iwhere F=—NR³. (S. L. Buchwald, et al, ibid.; J. H. Hartwig, ibid.) Forthe above example, R_(a) and R_(b) are independently hydrogen, alkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.

Scheme 2b illustrates a modification of Scheme 2a to synthesizepartially unsaturated compounds of Formula I. E represents—NQ_(a)Q_(b)R³—, —O-(D¹=D²=H), —S-(D¹=D²=H), —SO-(D¹=D²=H), or—SO₂-(D¹=D²=H), and R_(AA) represents —NH₂ or —NO₂. Compounds of formula2-4 are prepared as shown in Scheme 2. If R_(AA)=—NO₂, the nitro groupmust be reduced by a method that does not reduce olefins, such as ironand ammonium chloride. If R_(AA) of formula 2-4 is an amino group thenno step is necessary and compounds of formula 2-4 are also compounds offormula 2-7. To prepared compounds of formula 2-7 where E=—SO₂— or —SO—,the oxidation of the sulfide must be performed on compound 2-4 whereR_(AA)=—NO₂ as described above, followed by nitro reduction.III. Methods of Preparation

Scheme 3 illustrates the preparation of intermediates for the synthesisof compounds of Formula I, where ring A is pyridyl, and R⁵ is theoptional substitution on ring A or one of the heterocyclic substituentsas defined in Formula I. K=NH₂ or other functional groups such as NO₂,COOH or COOR which can eventually be converted to amino group by knownliterature methods such as reductions for NO₂ (as discussed forScheme 1) or Curtius rearrangement for COOH (for a review, see OrganicReactions, 3: 337 (1947)). L³ and L⁴ are halogens. (K═COOH can also beformed from K═COOR by simple base- or acid-catalyzed hydrolysis.)

In general, the selectivity and order in introducing R² and R⁵ can beachieved by the relative reactivity of the halogens L³ and L⁴ chosen incompound (3-1), the intrinsic selectivity of the heterocycle and/or thereaction conditions employed. An example of using the relativereactivity of the halogens L³ and L₄ in selectively introducing R² andR⁵ would include the situation where, in compounds of Formula 3-1 whereL³ is a fluoro group and L⁴ is a bromo group, selective displacement ofthe fluoro group by a nucleophile can be achieved followed bysubstitution of the remaining bromo group by metal-catalyzedsubstitution chemistry (such as Suzuki or Stille cross-couplingreactions as further outlined below). Similarly in compounds of Formula3-1 where one of L³ and L⁴ is an iodo group and the other is a bromo orchloro group, selective metal-catalyzed substitution chemistry (such asSuzuki or Stille cross-coupling reactions or Buchwald/Hartwig aminationsas further discussed below) on the iodo group can be achieved followedby replacement of the remaining bromo or chloro group by anothermetal-catalyzed substitution reaction.

As illustrated in Scheme 3, leaving group L³ in Formula 3-1 can be firstsubstituted to obtain compounds of Formula 3-3 or leaving group L⁴ canbe first substituted to obtain compound of Formula 3-2. Compounds 3-2 or3-3 can then be reacted to displace L³ or L⁴ to furnish the compound ofFormula 3-4.

Thus, a direct nucleophilic displacement or metal-catalyzed amination ofcompound of Formula 3-1 with a secondary amine, ammonia or a protectedamine such as tert-butyl carbamate (for review, see Modern AminationMethods: Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000), can be used tointroduce R⁵ in Formulae 3-2 or 3-3 where R⁵ is a primary or secondaryamine, amino group (NH₂), and amine equivalent or a protected aminogroup. Metal-catalyzed coupling of compound 3-1 with boronic acids orboronates esters (Suzuki reaction, M=boronic acid group or boronateester group) or with organotin compounds (Stille reaction, M=SnR₃, whereR=alkyl and the other substituents as defined above, as described inScheme I can provide compounds of Formulae 3-2 or 3-3.

Compound 3-2 can be further converted to compound 3-4 by ametal-catalyzed Suzuki or Stille coupling as described above. L⁴ incompound 3-3 also subsequently can be substituted with R⁵ to obtaincompounds of Formula 3-4, again, by a direct nucleophilic substitutionor metal-catalyzed reaction with a nucleophile or by the samemetal-catalyzed cross-coupling reaction as described above. When R⁵ inthe formulae (3-2, 3-3 or 3-4) is a protected amine and K not an aminogroup, it can be deprotected to unmask the amino functionality. Thisamino functionality can then be further derivatized as described inScheme 1. When the K group in Formula 3-4 is not an amino group (such asfunctionality described above), it can be converted to an amino groupaccording to known literature methods (see, for example ComprehensiveOrganic Transformations: Larock, R. S.; Wiley and Sons Inc., USA, 1999)and the resulting amine 3-5 can be employed in amide bond formationreactions as described in Scheme (1) to obtain the compounds in FormulaI. When K in Formula 3-4 is an amino group it can be directly used inamide coupling as described above.

Schemes 4a and 4b illustrate the preparation of intermediates to befurther modified according to Scheme 3 starting from amonohalo-substituted compound of Formulae 4-1 and 4-5 by introducing thesecond leaving group after the replacement of the first one has beencompleted. These can also be used for the synthesis of compounds ofFormula I where ring A is a pyridine and R⁵ is either the optionalsubstitution on Ring A or one of the heterocyclic substituents. As inScheme 3, the remaining positions on the pyridine ring can besubstituted as described in Formula I. K═NH₂ or other functional groupssuch as NO₂, COOH or COOR which can eventually be converted to aminogroup by known literature methods such as reductions or Curtiusrearrangement as described in Scheme 3. L³ and L⁴ are halogens. In thesecompounds, T is either H or is a functional group such as OH that can beconverted to leaving groups L³ or L⁴ such as halogen, triflate ormesylate by known literature methods (see, for example, Nicolai, E., etal., J. Heterocyclic Chemistry, 31, (73), (1994)). Displacement of L³ incompound of Formula 4-1 or L⁴ in Formula 4-5 by methods described inScheme 3, can yield compounds of Formulae 4-2 and 4-6. At this point,the substituent T of compounds 4-2 or 4-6 can be converted to a leavinggroup L⁴ or L³ (preferably a halogen) by standard methods to providecompounds of Formulae 4-3 and 4-5. For example, when T=OH, the preferredreagents to effect this transformation are thionyl chloride, PCl₅, POCl₃or PBr₃ (see, for examples, Kolder, den Hertog., Recl. Trav. Chim.Pays-Bas; 285, (1953), and Iddon, B, et. al., J. Chem. Soc. PerkinTrans. 1., 1370, (1980)). When T=H, it can be directly halogenated(preferably brominated) to provide compounds of Formulae 4-3 or 4-7(see, for example, Canibano, V. et al., Synthesis, 14, 2175, (2001)).The preferred conditions for bromination are NBS in a suitable solventsuch as DCM or acetonitrile.

The compounds of Formulae 4-3 or 4-7 can be converted to compounds ofFormulae 4-4 or 4-8 by introduction of the remaining groups R² or R⁵,respectively, by the methods described above and then on to compounds ofFormula I, by the methods described in Scheme 3 for conversion ofcompounds of Formulae 3-4 and 3-5 to compounds of Formula I.

EXAMPLE 1 5-Cyano-furan-2-carboxylic acid

To a flask with a stir bar and Vigreaux column under Ar was added2-formyl-5-furancarboxylic acid (2.8 g, 20 mmol), hydroxylaminehydrochloride (2.7 g, 40 mmol), and dry pyridine (50 mL). The mixturewas heated to 85° C., acetic anhydride (40 mL) was added and the mixturewas stirred for 3 h. After cooling to 60° C., water (250 mL) was addedand the mixture was stirred at RT for 70 h. The mixture was acidified topH 2 with concentrated hydrochloric acid and extracted with 3:1dichloromethane-isopropanol (8×100 mL). The combined organic layers werewashed with water (100 mL), brine (100 mL), dried over anh sodiumsulfate and concentrated in vacuo to afford the title compound as a tansolid (1.26 g, 46%). ¹H-NMR (CD₃OD; 400 MHz): δ 14.05 (br s, 1H), 7.74(d, 1H, J=3.8 Hz), 7.42 (d, 1H, J=3.8 Hz).

EXAMPLE 2 4-Cyano-1H-pyrrole-2-carboxylic acid

The title compound was prepared by the literature procedure (Loader andAnderson, Canadian J. Chem. 59: 2673 (1981)). ¹H-NMR (CDCl₃; 400 MHz): δ12.70 (br s, 1H), 7.78 (s, 1H), 7.13 (s, 1H).

EXAMPLE 34-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A flask charged with imidazole-4-carbonitrile (0.5 g, 5.2 mmol)(Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl)(0.95 mL, 5.3 mmol), K₂CO₃ (1.40 g, 10.4 mmol), and acetone (5 mL) wasstirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) andwashed with water (20 mL) and brine (20 mL) and the organic layer driedover MgSO₄. The crude product was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the titlecompound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. forC₁₀H₁₇N₃OSi, 224.1 (M+H), found 224.1.

b)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4carbonitrile

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g,3.1 mmol) (as prepared in the previous step) in CCl₄ (10 mL) was addedNBS (0.61 g, 3.4 mmol) and AIBN (cat), and the mixture heated at 60° C.for 4 h. The reaction was diluted with EtOAc (30 mL) and washed withNaHCO₃ (2×30 mL) and brine (30 mL) and the organic layer was dried overNa₂SO₄ and then concentrated. The title compound was eluted from a 20-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.73 g (77%) of ayellow solid. Mass spectrum (CI (CH₄), m/z) Calcd. for C₁₀H₁₆BrN₃OSi,302.0/304.0 (M+H), found 302.1/304.1.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile(0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at−40° C. was added drop wise a solution of 2M i-PrMgCl in THF (1 mL). Thereaction was allowed to stir for 10 min at −40° C. and then cooled to−78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. Thereaction allowed to attain RT and stirred for 1 h. The reaction wasquenched with satd aq NH₄Cl, diluted with EtOAc (20 mL) and washed withbrine (2×20 mL), and the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.4 g (74%) of a colorless oil.Mass spectrum (ESI, m/z): Calcd. for C₁₃H₂₁N₃O₃Si, 296.1 (M+H), found296.1.

d)4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (0.4 g, 1.3 mmol) (as prepared in the previous step) inethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and the reactionwas stirred for 10 min and then concentrated to give 0.40 g (100%) ofthe title compound as a yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ 7.98 (s,1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). Massspectrum (ESI-neg, m/z) Calcd. for C₁₁H₁₇N₃O₃Si, 266.1 (M-H), found266.0.

EXAMPLE 4 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide

a) 1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine

2-Bromo-4-fluoronitrobenzene (949 mg, 4.31 mmol) was added in twoportions to neat N-methypiperazine (8 mL) at 0° C. and allowed to warmto room temperature. The reaction was heated to 60° C. for 1 h, and thenit was diluted with 50 mL of EtOAc and poured into H₂O (50 mL). Thelayers were separated and the organic layer was washed with satd aqNaHCO₃, dried (Na₂SO₄), and concentrated in vacuo to afford 580 mg (45%)of the title compound as a yellow solid: Mass spectrum (ESI, m/z):Calcd. for C₁₁H₁₄BrN₃O₂, 300.0 (M+H), found 300.1.

b) 4,4,5,5-Tetramethyl-2-(3-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane

To a stirred solution of 2-bromo-3-methythiophene (337 mg, 1.9 mmol) in8 mL of THF at −40° C. was added n-BuLi (0.8 mL, 2.5 M/hexanes), and thereaction was allowed to stir for 30 min. At this time2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol)was added, and the reaction was allowed to warm to ambient temperature,and stirring was continued for 1 h. The reaction was then cooled to 0°C. and quenched with satd aq NaHCO₃ (10 mL). The mixture was poured intoEtOAc (100 mL), washed with H₂O (2×50 mL), dried (Na₂SO₄) andconcentrated in vacuo. Purification of the residue by silica gelpreparative thin layer chromatography (20% EtOAc-hexanes) afforded 224mg (53%) of the title compound as an oil. ¹H- NMR (CDCl₃; 400 MHz): δ1.36 (s, 12H), 2.5 (s, 3H), 6.99 (d, 1H, J=4.8 Hz), 7.50 (d, 1H, J=4.8Hz).

c) 1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine

To a flask containing 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (68mg, 0.2 mmol, as prepared in Example 4, step (a)),4,4,5,5-tetramethyl-2-(3-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane (61mg, 0.27 mmol, as prepared in the previous step) and Pd(PPh₃)₄ (14 mg, 6mol %) was charged toluene (3 mL), ethanol (3 mL) and 2M Na₂CO₃ (4 mL).The resultant mixture was heated at 80° C. for 2 h and then poured intoEtOAc (25 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel preparative thin layerchromatography (EtOAc) afforded 40 mg (63%) of the title compound as alight yellow solid. Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₉N₃O₂S,318.1 (M+H), found 318.2.

d) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide

1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg5% Pd—C in MeOH (5 mL) under H₂ (1 atm) for 2 h. The reaction wasfiltered through Celite and concentrated in vacuo to afford 40 mg (72%)of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine asa brown solid, which was used immediately without further purification.Using a procedure similar to Example 9, step (c),4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonylchloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in thepresence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the titlecompound as a yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 2.13 (s, 3H),2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8Hz), 7.06 (d, 1H, J=5.1Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H),8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₂N₄O₂S, 407.1 (M+H), found 407.1.

EXAMPLE 5 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenyl]-amide

a) 4,4,5,5-Tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane

Using a procedure similar to Example 4, step (b),3-bromo-4-methylthiophene (571 mg, 3.2 mmol) was treated with n-BuLi(1.41 mL, 2.5M/hexanes) and then allowed to react with2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol)to afford 189 mg (26%) of the title compound as a colorless oil. ¹H-NMR(CDCl₃; 400 MHz): δ 1.32 (s, 12H), 2.42 (s, 3H), 6.90-6.91 (m, 1H), 7.84(d, 1H, J=2.9 Hz).

b) 1-Methyl-4-[3-(4-methyl-thiophen-3-yl)-4-nitro-phenyl]-piperazine

Using a procedure similar to Example 4, step (c),1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (162 mg, 0.54 mmol),4,4,5,5-tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane (145mg, 0.64 mmol) and Pd(PPh₃)₄ (37 mg, 6 mol %) were allowed to react toafford 108 mg (71%) of the title compound as a yellow solid. ¹H-NMR(CDCl₃; 400 MHz): δ 2.02 (s, 3H), 2.37 (s, 3H), 2.55-2.57 (m, 4H),3.42-3.45 (m, 4H), 6.66 (d, 1H, J=2.8 Hz), 6.87 (s, 1H), 6.99-7.00 (m,1H), 7.09 (d, 1H, J=3.2 Hz), 8.13 (d, 1H, J=9.2 Hz).

c) 4(4-Methyl-piperazin-1-yl)-2-(4methyl-thiophen-3-yl)-phenylamine

Using a procedure similar to Example 4, step (d),1-methyl-4-[3-(4-methyl-thiophen-3-yl)-4-nitro-phenyl]-piperazine (100mg, 0.32 mmol) was stirred with 80 mg 5% Pd—C under H₂ to afford 82 mg(89%) of the title compound as a dark oil, which was used immediatelywithout further purification spectrum (ESI, m/z): Calcd. for C₁₆H₂₁N₃S,288.15 (M+H), found 288.1.

d) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenyl]-amide

Using a procedure similar to Example 9, step (c),5-cyano-furan-2-carbonyl chloride (64 mg, 0.41 mmol, as prepared inExample 9, step (c)) was allowed to react with4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenylamine (80mg, 0.27 mmol, as prepared in the previous step) in the presence of DIEA(0.10 mL, 0.59 mmol) to afford 25.8 mg (24%) of the title compound as ayellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 2.09 (s, 3H), 2.37 (s, 3H),2.59-2.60 (m, 4H), 3.24-3.26 (m, 4H), 6.83 (d, 1H, J=2.9 Hz), 6.98-7.06(m, 2H), 7.14-7.21 (m, 3H), 7.96 (s, 1H), 8.32 (d, 1H, J=9.0 Hz). Massspectrum (ESI, m/z): Calcd. for C₂₂H₂₂N₄O₂S, 407.1 (M+H), found 407.1.

EXAMPLE 6 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-I-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl)-amidetrifluoroacetic acid salt

a) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2,2-dimethyl-[1,3]dioxan-5-yl)-piperidin-4-yl]-phenyl)-amide

To a slurry of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-arnide trifluoroacetic acidsalt (81 mg, 0.16 mmol, as prepared in Example 14, step (b)) in CH₂Cl₂(3 mL) was added NEt₃ (33 μL, 0.24 mmol). The solution was then treatedwith 2,2-dimethyl-[1,3]dioxan-5-one (31 mg, 0.24 mmol) and the reactionwas allowed to stir for 3 h. At this time NaBH(OAc)₃ (51 mg, 0.24 mmol)was added in one portion, and the reaction was allowed to stir for anadditional 4 h. The reaction was diluted with H₂O (10 mL) and extractedwith EtOAc (2×25 mL). The organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel preparative thin layerchromatography (10% MeOH—CHCl₃) afforded 22 mg (28%) of the titlecompound as an off-white semi-solid. Mass spectrum (ESI, m/z): Calcd.for C₂₈H₃₅N₅O₃, 490.2 (M+H), found 490.6.

b) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl]-amidetrifluoro-acetic acid

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2,2-dimethyl-[1,3]dioxan-5-yl)-piperidin-4-yl]-phenyl}-amide(22 mg, 0.04 mmol, as prepared in the previous step) in THF—H₂O (1 mL,4:1 v/v) was added TFA (0.4 mL), and the reaction was allowed to stirfor 1 h. Removal of the solvent under vacuum afforded 14 mg (60%) of thetitle compound as an amber foam. ¹H-NMR (CD₃OD, 400 MHz): δ 1.78-1.90(m, 4H), 2.03-2.16 (m, 3H), 2.29 (br s, 4H), 2.88-2.96 (m, 1H),3.37-3.40 (m, 1H), 3.46-3.53 (m, 2H), 3.74-3.78 (m, 3H), 5.83 (s, 1H),7.13 (d, 1H, J=2.0 Hz), 7.22 (dd, 1H, J=2.0, 8.4 Hz), 8.03 (s, 1H), 8.17(d, 1H, J=8.4 Hz); Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₁N₅O₃,450.2 (M+H), found 450.2.

EXAMPLE 7 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-I-enyl-4-[1-(2-morpholin-4-yl-acetyl)-piperidin-4-yl]-phenyl)-amide

To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringeand stirring was continued for 3 h. Concentration in vacuo afforded 122mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture ofmorpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol),4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) andPyBroP (93 mg, 0.19 mmol) in CH₂Cl₂ (4 mL) was added DIEA (51 μL, 0.29mmol) and the reaction was allowed to stir overnight. The reaction wasdiluted with CH₂Cl₂ (50 mL), washed with H₂O (2×25 mL), dried (Na₂SO₄)and concentrated in vacuo. Purification of the crude product by silicagel preparative TLC afforded 8.1 mg (12%) of the title compound as awhite solid. ¹H-NMR (CDCl₃; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m,4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (brs, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s,1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1H), 8.27 (d, 1H, J=8.1Hz),9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₄N₆O₃, 503.27(M+H), found 503.1.

EXAMPLE 8 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-phenyl)-amide

To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl esterexactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To thestirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction wasallowed to stir overnight. The reaction was diluted with H₂O (10 mL) andextracted with EtOAc (2×25 mL). The combined organic extracts were dried(Na₂SO₄), concentrated in vacuo and the crude product was purified bysilica gel preparative TLC to afford 10.4 mg (6%) of the title compoundas a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 1.49-1.93 (m, 5H),2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m,4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m,2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13(m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Massspectrum (ESI, m/z): Calcd. for C₂₉H₃₆N₆O₃, 517.28 M+H), found 517.3.

EXAMPLE 9 5-Cyano-furan-2-carboxylic acid [2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

a) 1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine

To a cooled (0° C.) solution of 1.00 g (4.55 mmol) of2-bromo-4-fluoronitrobenzene (Oakwood) in 12 mL of EtOH was added 1.52mL (13.7 mmol) of piperidine. The solution was stirred at 0° C. for 0.5h and then at 60° C. for 4 h. The mixture was concentrated in vacuo,dissolved in EtOAc (60 mL), washed with water (3×100 mL) and brine (100mL), and dried (Na₂SO₄). Concentration in vacuo and chromatography on a50-g silica SPE column with 1-3% MeOH-dichloromethane afforded 1.06 g(77%) of the title compound as a tannish yellow solid. Mass spectrum(ESI, m/z): Calcd. for C₁₁H₁₄BrN₃O₂, 300.0 (M+H, ⁷⁹Br), found 300.1.

b) 1-Methyl-4-(2 ′-methyl-6-nitro-biphenyl-3-yl)-piperazine

A mixture of 200mg (0.666 mmol)1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in theprevious step), 136 mg (0.999 mmol) and 77.0 mg (0.0666 mmol) oftetrakis(triphenylphosphine)palladium (0) under Ar was added 4.0 mL ofdegassed dimethoxyethane (DME) and 400 μL (0.799 mmol) of 2.0 M aqNa₂CO₃. The mixture was heated with stirring under Ar at 80° C. for 14h. The cooled (RT) mixture was concentrated and chromatographed on a10-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1).The product fractions were treated with 80 mg of decolorizing carbon,filtered, concentrated, and then rechromatographed on a similar columnwith 1-3% EtOH-dichloromethane to afford 265 mg of the title compound asa yellow resin (75% purity by ¹H-NMR as a mixture withtriphenylphosphine) that was used in the following reaction withoutfurther purification: Mass spectrum (ESI, m/z): Calcd. for C₁₁H₂₁N₃O₃,312.2 (M+H), found 312.2.

c) 5-Cyano-furan-2-carboxylic acid[2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

A mixture of 140 mg (0.337 mmol based on 75% purity) of1-methyl-4-(2′-methyl-6-nitro-biphenyl-3-yl)-piperazine (as prepared inthe previous step) and 70 mg of 10% palladium on carbon (Degussa typeE101-NE/W, Aldrich, 50% by weight water) in 5 mL of THF was stirredvigorously under a balloon of hydrogen for 1 h. The mixture was filtered(Celite), washed with dichloromethane (2×2 mL), and the solution of theresulting aniline was placed under Ar and used immediately in thefollowing reaction.

Simultaneously to the above reduction, 55.4 mg (0.404 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 2.5 mL ofanh dichloromethane under a CaSO₄ drying tube was treated with 52.9 μL(0.606 mmol) of oxalyl chloride followed by 10 μL of anh DMF. Thesolution was stirred for 25 min and quickly concentrated in vacuo at20-25° C. The resulting 5-cyano-furan-2-carbonyl chloride was placedunder high vacuum for 2-3 min and then immediately placed under Ar,cooled to 0° C. in an ice bath, and treated with the aniline solutionproduced above followed by 141 μL (0.808 mmol) ofN,N-diisopropylethylamine (DIEA). After stirring for 30 min at RT, themixture was concentrated in vacuo, and the resulting residue waschromatographed on a 20-g silica SPE column with 2-10%EtOH-dichloromethane to give a yellow resin (which was crystallized fromEtOAc-hexane) to afford 17.2 mg (13%) of the pure title compound as ayellow solid along with 70.3 mg of impure title compound. The impurefraction was dissolved in 50 mL of EtOAc, washed with satd aq NaHCO₃-1 MK₂CO₃ (1:1, 2×20 mL) and brine (20 mL), dried (Na₂SO₄) and concentratedto afford 43.4 mg (32%) additional title compound as a crystallineyellow solid (total yield 45%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.32 (d, 1H,J=9.0 Hz), 7.73 (br s, 1H), 7.34-7.54 (m, 3H), 7.25 (d, 1H, J=7.7 Hz),7.12, 7.14 (AB q, 2H, J=3.7 Hz), 7.01 (dd, 1H, J=9.0, 2.8 Hz), 3.25-3.27(m, 4H), 2.59-2.62 (m, 4H), 2.38 (s, 3H), and 2.15 (s, 3H). Massspectrum (ESI, m/z): Calcd. for C₂₁H₂₄N₄O₃, 401.2 (M+H), found 401.1.

EXAMPLE 10 5-Cyano-furan-2-carboxylic acid[2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

a) 1-(2′-Fluoro-6-nitro-biphenyl-3-yl)-4-methyl-piperazine

The procedure of Example 9, step (b) was followed using 75.0 mg (0.250mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared inExample 9, step (a)), 136 mg (0.999 mmol) 2-fluorophenylboronic acid,26.8 mg (0.0232 mmol) of tetrakis(triphenylphosphine)palladium (0) and400 μL (0.799 mmol) of 2.0 M aq Na₂CO₃ in DME except the mnixture washeated for 22 h. Chromatography on a 5-g silica SPE column with 1-5%MeOH in dichloromethane-hexane (1:1) afforded 95.0 mg of the titlecompound (76% purity by ¹H-NMR as a mixture with triphenylphosphine) asa yellow resin that was used in the following reaction without furtherpurification. Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₈FN₃O₃, 316.1(M+H), found 316.2.

b) 5-Cyano-furan-2-carboxylic acid[2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

The procedure of Example 9, step (c) was followed using 93.2 mg (0.225mmol based on 76% purity) of1-(2′-fluoro-6-nitro-biphenyl-3-yl)-4-methyl-piperazine (as prepared inthe previous step), 46 mg of 10% palladium on carbon, 37.0 mg (0.270mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 35.3μL (0.405 mmol) of oxalyl chloride, 5.0 μL of anh DMF, and 94.1 μL(0.540 mmol) of DIEA. Chromatography on a 5-g silica SPE column with1-4% MeOH-dichloromethane afforded 69.8 mg (77%) of the title compoundas a yellow resin. ¹H-NMR (CDCl₃; 400 MHz): δ 8.04 (d, 1H, J=9.0 Hz),7.93 (br s, 1H), 7.434-7.48 (m, 1H), 7.37 (td, 1H, J=7.5, 1.8 Hz),7.22-7.31 (m, 2H), 7.13, 7.18 (AB q, 2H, J=3.7 Hz), 7.02 (dd, 1H, J=9.0,2.9 Hz), 6.88 (d, 1H, J=2.9 Hz), 3.24-3.27 (m, 4H), 2.57-2.60 (m, 4H),and 2.36 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₁FN₄O₂,405.2 (M+H), found 405.2.

EXAMPLE 11 5-Cyano-furan-2-carboxylic acid[2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide

a) 1-(3-Cyclohex-1-enyl-4-nitro-phenyl)-4-methyl-piperazine

A mixture of 102 mg (0.340 mmol)1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example9, step (a)), 59.7 mg (0.474 mmol) cyclohexen-1-ylboronic acid, 43.8 mg(0.0379 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar wastreated with 206 μL (0.412 mmol) of 2.0 M degassed aq Na₂CO₃, 0.6 mLdegassed anh toluene and 0.2 mL degassed anh EtOH and the mixture washeated at 100° C. for 21 h. After cooling to RT, the mixture was pouredinto EtOAc (10 mL), washed with brine (10 mL), dried (Na₂SO₄) andconcentrated in vacuo. Chromatography on a 5-g silica SPE column with1-3% EtOH in dichloromethane afforded 126 mg of the title compound (74%purity by RP-HPLC (C18 column) as a mixture with triphenylphosphine) asa yellow oil that was used in the following reaction without furtherpurification. Mass spectrum (ESI, m/z): Calcd. for C₁₇H₂₃N₃O₃, 302.2(M+H), found 302.2.

b) 5-Cyano-furan-2-carboxylic acid[2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide

To 122 mg (0.299 mmol based on 74% purity) of1-(3-cyclohex-1-enyl-4-nitro-phenyl)-4-methyl-piperazine (as prepared inthe previous step) in 5.0 mL of EtOH-water (2:1) was added 83.8 mg (1.50mmol) of iron powder and 160 mg (2.99 mmol) of NH₄Cl and the mixturerefluxed under Ar for 12 h. An additional 83.8 mg (1.50 mmol) of ironpowder was added, and the mixture was refluxed for 1 h. The mixture waspoured into EtOAc (12 mL), filtered (Celite), washed with EtOAc (2×4mL), concentrated in vacuo and dissolved in anh THF (4.0 mL). Theresulting aniline solution was placed under Ar and used immediately inthe following reaction.

61.6 mg (0.449 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared inExample 1) in 2.5 mL of anh dichloromethane under a CaSO₄ drying tubewas treated with 60.0 μL (0.688 mmol) of oxalyl chloride followed by 10μL of anh DMF. The solution was stirred for 25 min and quicklyconcentrated in vacuo at 20-25° C. The residue was placed under highvacuum for 2-3 min and then immediately placed under Ar, cooled to 0° C.in an ice bath and treated with the aniline solution produced abovefollowed by 104 μL (0.598 mmol) of DIEA. After stirring 30 min at RT,the mixture was concentrated in vacuo, dissolved in EtOAc (20 mL),washed with 1M K₂CO₃ (2×10 mL) and brine (10 mL), dried (Na₂SO₄) andconcentrated in vacuo. The resulting residue was chromatographed on a10-g silica SPE column with 1-4% MeOH-dichloromethane to give a yellowresin which was then crystallized from Et₂O-hexane to afford 84.7 mg(72%) of the title compound as a crystalline yellow solid. ¹H-NMR(CDCl₃; 400 MHz): δ 8.57 (br s, 1H), 8.26 (d, 1H, J=9.0 Hz), 7.20, 7.23(AB q, 2H, J=3.7 Hz), 6.86 (dd, 1H, J=9.0, 2.9 Hz), 6.74 (d, 1H, J=2.9Hz), 5.84-5.85 (m, 1H), 3.20-3.22 (m, 4H), 2.57-2.59 (m, 4H), 2.36 (s,3H), 2.23-2.30 (m, 4H) and 1.79-1.84 (m, 4H). Mass spectrum (ESI, m/z):Calcd. for C₂₃H₂₆N₄O₂, 391.2 (M+H), found 391.2.

EXAMPLE 12 5-Cyano-furan-2-carboxylicacid[2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl-amide

a) 1-[3-(3,6-Dihydro-2H-pyran-4-yl)-4-nitro-phenyl]-4-methyl-piperazine

1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example9, step (a)) (225.1 mg, 0.79 mmol), K₂CO₃ (310.9 mg, 2.25 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(Murata, M., et al, Synthesis, 778, (2000)) (157 mg, 0.75 mmol) indioxane (5 mL) was heated at 80° C. overnight under Ar. The reactionmixture was allowed to cool to RT, concentrated, and the resultingresidue was chromatographed on silica (10% EtOAc/hexane-20% MeOH/EtOAc)to obtain the title compound (82 mg, 36%). ¹H-NMR (CDCl₃; 400 MHz): δ8.04 (d, 1H, J=9.4 Hz), 6.78 (dd, 1H, J=9.4, 2.6 Hz), 6.58 (m, 1H, J=2.6Hz), 5.58 (m, 1H), 4.34 (m, 2H), 3.95 (t, 2H, J=5.3 Hz), 3.46 (m, 4H),2.57 (m, 4H), 2.38 (s, 3H), 2.30 (m, 2H).

b) 5-Cyano-furan-2-carboxylicacid[2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl-amide

1-[3-(3,6-Dihydro-2H-pyran-4-yl)-4-nitro-phenyl]-4-methyl-piperazine (asprepared in previous step) (80 mg, 0.26 mmol) was converted to thecorresponding amine using a procedure similar to Example 4, step (d),and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 9, step (c) (obtained from 137 mg, 1.00 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH₂Cl₂ (2mL) at 0° C. The product was isolated by flash chromatography on silica(50% EtOAc/hexane-10% MeOHIEtOAc) to obtain the title compound (62.2 mg,60%). ¹H-NMR (CDCl₃; 400 MHz): 6 8.35 (br s, 1H), 8.12 (d, 1H each,J=8.76 Hz), 7.24 (d, 1H, J=5.08 Hz), 7.19 (d, 1H, J=5.08 Hz), 6.88 (dd,1H, J=8.76, 2.7 Hz), 6.73 (d, 1H, J=2.7 Hz), 5.88 (br s, 1H), 4.34 (m,2H), 3.94 (t, 2H, J=5.3 Hz), 3.23 (m, 4H), 2.59 (m, 4H), 2.38 (br s,5H). LC-MS (ESI, m/z): Calcd. for C₂₂H₂₄N₄O₃, 393.1 (M+H), found 393.2.

EXAMPLE 13 4-Cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

a) 4-(4-Amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

The title compound was prepared by Suzuki coupling of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (Synthesis, 993, (1991)) according to the procedure inExample 35, step (b). Mass spectrum (ESI, m/z): Calcd. for C₁₆H₂₂N₂O₂,275.2 (M+H), found 275.1.

b) 4-(4-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.35 g, 1.2 mmol) (as prepared in the previousstep) in methanol was hydrogenated over 10% Pd/C at 20 psi for 1 h. Thesolution was filtered and concentrated to give 0.35 g (100%) of thetitle compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₄N₂O₂, 277.2 (M+H), found 277.1.

c) 4-(4-Amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butylester

To a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (0.20 g, 0.71 mmol) (as prepared in the previous step)in DCM (3 mL) was added N-bromosuccinimide (NBS) (0.13 g, 0.71 mmol),and the reaction stirred at RT for 10 h. The reaction was diluted withEtOAc (10 mL) and washed with NaHCO₃ (2×10 mL) and brine (10 mL).Concentration of the organic layer gave 0.26 g (100%) of the titlecompound as a yellow foam. Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₃BrN₂O₂, 355.1 (M+H), found 355.1.

d) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

A flask was charged with4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester(0.13 g, 0.36 mmol) (as prepared in the previous step), cyclohex-1-enylboronic acid (0.060 g, 0.48 mmol), Pd(PPh₃)₄ (0.04 g, 10 mol %), aqueous2M Na₂CO₃ (1.5 mL), ethanol (1.5 mL), and toluene (3 mL), and heated at80° C. for 3 h. The reaction was diluted EtOAc (10 mL), washed withNaHCO₃ (2×10 mL) and brine (10 mL), and the organic layer was dried overNa₂SO₄ and then concentrated. The title compound was eluted from a 20-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.10 g (85%) of thetitle compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. forC₂₂H₃₂N₂O₂, 357.2 (M+H), found 357.1.

e) 4-Cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

A flask was charged with4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (0.050 g, 0.14 mmol) (as prepared in the previousstep), 4-cyano-1H-pyrrole-2-carboxylic acid (0.019 g, 0.14 mmol)(asprepared in Example 2), EDCI (0.040 g, 0.21 mmol), HOBt (0.019 g, 0.14mmol), DIEA (0.073 mL, 0.42 mmol), and DCM (0.5 mL) and stirred at 25°C. for 10 h. The reaction was loaded directly on a 10-g solid phaseextraction (SPE) cartridge (silica) and the resulting intermediate waseluted with 30% EtOAc/hexane. This compound was stirred at RT for 1 h in50% TFA/DCM (2 mL) and then concentrated and purified by RP-HPLC (C18),eluting with 30-50% CH₃CN in 0.1% TFA/H₂O over 12 min to give the titlecompound (0.052 g, 77%). ¹H-NMR (400 MHz, CD₃OD): δ 7.59 (s, 1H), 7.50(d, 1H), 7.22 (d, 1H), 7.16 (m, 2H), 5.74 (m, 1H), 3.54. (m, 2H), 3.16(m, 2H), 2.94 (m, 1H), 2.29 (m, 2H), 2.15 (m, 4H), 1.92 (m, 2H), 1.72(m, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₆N₄O, 375.2 (M+H),found 375.1.

EXAMPLE 14 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

a)4-(4-[4-Cyano-]-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (3.34 g, 10.9 mmol) (as prepared in Example 3, step (d))in 20 mL DCM was added DIEA (3.8 mL, 21.8 mmol) and PyBroP (5.6 g, 12.0mmol), and the reaction stirred at 25° C. for 15 min. A solution of4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (3.9 g, 10.9 mmol) (as prepared in Example 13, step(d)) in 10 mL DCM was added and the reaction stirred for 8 h at 25° C.The reaction was diluted EtOAc (60 mL) and washed with NaHCO₃ (2×60 mL)and brine (100 mL) and the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was purified by flash chomatography(silica gel, 2% EtOAc/DCM) to give 5.5 g (85%) of the title compound asa yellow oil. Mass spectrum (ESI, m/z): Calcd. for C₃₃H₄₇N₅O₄Si, 606.2(M+H), found 606.2.

b) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (1.5 g, 2.5 mmol) (as prepared in the previousstep) in 10 mL of DCM and 0.3 mL EtOH was added 3 mL of TFA and thesolution stirred for 3 h at 25° C. The reaction was diluted with 5 mL ofEtOH and then concentrated. The residue was crystallized from methanoland ethyl ether to give 0.85 g (70%) of the title compound as a whitesolid. ¹H-NMR (400 MHz, CD₃OD) δ 8.18 (d, 1H), 8.04 (s, 1H), 7.22 (dd,1H), 7.12 (d, 1H), 5.76 (m, 1H), 3.54. (m, 2H), 3.16 (m, 2H), 2.92 (m,1H), 2.30 (m, 4H), 2.10 (m, 2H), 1.75 (m, 6H). Mass spectrum (ESI, m/z):Calcd. for C₂₂H₂₅N₅O, 376.2 (M+H), found 376.2.

EXAMPLE 15 4-Cyano-1H-pyrrole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide

The title compound was prepared from 4-cyano-1H-pyrrole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (as prepared in Example 13, step (e)) according to theprocedure in Example 37. ¹H-NMR (400 MHz, CDCl₃) δ 10.82 (s, 1H), 8.28(d, 1H), 8.18 (s, 1H), 7.48 (d, 1H), 7.16 (dd, 1H), 7.02 (s, 1H), 6.72(s, 1H), 5.88 (m, 1H), 4.82 (m, 1H), 3.98. (m, 1H), 3.20 (m, 1H), 2.70(m, 2H), 2.29 (m, 4H), 2.18 (s, 3H), 1.80 (m, 8H). Mass spectrum (ESI,m/z): Calcd. for C₂₅H₂₈N₄O₂, 417.2 (M+H), found 417.1.

EXAMPLE 16 4-Cyano-1H-imidazole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (as prepared in Example 13, step (b)) according to theprocedure in Example 37: ¹H-NMR (400 MHz, CDCl₃) δ 13.12 (br s, 1H),9.58 (s, 1H), 8.34 (d, 1H), 7.76 (s, 1H), 7.21 (dd, 1H), 7.05 (d, 1H),5.86 (s, 1H), 4.84 (m, 2H), 4.00 (m, 1H), 3.22 (m, 1H), 2.72 (m, 2H),2.30 (m, 4H), 2.21 (s, 3H), 1.80 (m, 8H). Mass spectrum (ESI, m/z):Calcd. for C₂₄H₂₇N₅O₂, 418.2 (M+H), found 418.1.

EXAMPLE 17 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amidetrifluoroacetic acid salt

The title compound was prepared from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (d)) and4-[4-amino-3-(4-methyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (prepared according to the procedure in Example13, step (d), substituting 4-methyl-1-cyclohex-1-enyl boronic acid forcyclohex-1-enyl boronic acid) according to the procedure for Example 14:¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.04 (s, 1H), 7.22 (dd, 1H),7.12 (d, 1H), 5.80 (m, 1H), 3.54. (m, 2H), 3.18 (m, 2H), 2.94 (m, 1H),2.30 (m, 3H), 2.12 (m, 2H), 1.92 (m, 5H), 1.54 (m, 1H), 1.12 (d, 3H).Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₇N₅O, 390.2 (M+H), found390.2.

EXAMPLE 18 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

The title compound was prepared from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (d)) and4-(4-amino-3-cyclopent-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (prepared according to the procedure in Example 13,step (d), substituting cyclopenten-1-yl boronic acid for cyclohex-1-enylboronic acid) according to the procedure for Example 14. ¹H-NMR (400MHz, DMSO-d₆) δ 14.25 (br s, 1H), 10.00 (s, 1H), 8.36 (s, 1H), 7.72 (d,1H), 7.18 (m, 2H), 6.06 (s, 1H), 4.12 (m, 1H), 3.42 (m, 2H), 3.18 (m,2H), 3.00 (m, 3H), 2.80 (m, 2H), 1.92 (m, 5H). Mass spectrum (ESI, m/z):Calcd. for C₂₁H₂₃N₅O, 362.2 (M+H), found 362.2.

EXAMPLE 19

An alternate method for the synthesis of the intermediate described inExample 1 is described below.

5-Cyano-furan-2-carboxylic acid

A 250-mL, three-neck, round-bottom flask equipped with a mechanicalstirrer, a heating mantle, and a condenser was charged with5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and themixture was heated to 85° C. Acetic anhydride (40 mL) was added and thereaction was stirred at 85° C. for 3 h, after which time the solvent wasevaporated at 40° C. under reduced pressure. The residue was dissolvedin water, basified with 2.0 N NaOH solution to pH 9, and extracted with4:1 dichloromethane/2-propanol until the pyridine was completely removed(5×200 mL). The aqueous solution was then acidified with 2.0 N HClsolution to pH 2, saturated with solid NaCl, and extracted with 4:1dichloromethane/2-propanol (5×200 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated in vacuo to dryness. The residuewas crystallized from dichloromethane to give 6.80 g of the titlecompound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. forC₆H₃NO₃, 136.0 (M−H), found 136.1. The ¹H NMR spectrum was consistentwith the assigned structure.

EXAMPLE 20 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-phenyl)-amide

A flask was charged with methanesulfonyl-acetic acid (14 mg, 0.10 mmol),EDCI (30 mg, 0.15 mmol), HOBt (14 mg, 0.10 mmol), DIEA (36 μL, 0.20mmol) and 0.5 mL DCM and stirred at 25° C. After 10 min, a solutioncontaining 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (40 mg, 0.08mmol) (as prepared in Example 20, step (b)) and NEt₃ (14 μL, 0.09 mmol)in 0.5 mL DCM was added and the reaction allowed to proceed for 10 h at25° C. The reaction mixture was loaded on a 5-g SPE cartridge (silica)and the title compound was eluted with 10% EtOH/EtOAc to give 10 mg(25%) of a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 11.60 (br s, 1H),9.52 (s, 1H), 8.30 (d, 1H), 7.74 (s, 1H), 7.60 (dd, 1H), 7.03 (d, 1H),5.86 (m, 1H), 4.84 (m, 1H), 4.18 (s, 2H), 4.12 (m, 1H), 3.32 (m, 1H),3.20 (s, 3H), 2.82 (m, 2H), 2.30 (m, 4H), 1.98 (m, 2H), 1.84 (m, 5H),1.72 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₂₉N₅O₄S, 496.2(M+H), found 496.2.

EXAMPLE 21 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (88 mg, 0.18mmol) (as prepared in Example 14, step (b)), pyridine-2-carbaldehyde (17μL, 0.21 mmol), NEt₃ (30 μL, 0.21 mmol), sodium triacetoxyborohydride(56 mg, 0.25 mmol) and 0.8 mL of 1,2-dichloroethane and stirred for 10 hat 25° C. The solvent was evaporated, and the title compound waspurified by RP-HPLC (C18), eluting with 30-50% CH₃CN in 0.1% TFA/H₂Oover 20 min to give 81 mg (78%) of a white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s,1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.88 (dd, 1H), 7.58 (d, 1H), 7.52 (m,1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.76 (m, 1H), 4.56 (s, 2H), 3.40 (m,2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.20 (m, 4H), 2.00 (m, 4H), 1.72 (m,4H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₀N₆O, 467.2 (M+H), found467.2.

EXAMPLE 22 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

This compound was prepared according to the procedure in Example 21 from4-cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide (asprepared in Example 17) and pyridine-2-carbaldehyde. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s,1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.52 (m,1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.74 (m, 1H), 4.56 (s, 2H), 3.40 (m,2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.48-2.22 (m, 3H), 2.18-2.06 (m, 4H),1.98-1.82 (m, 3H), 1.52 (m, 1H), 1.02 (s, 3H). Mass spectrum (ESI, m/z):Calcd. for C₂₈H₃₂N₆O, 481.2 (M+H), found 481.2.

EXAMPLE 23 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

This compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as preparedin Example 18) and 1-methyl-1H-imidazole-2-carbaldehyde according to theprocedure in Example 21. ¹H-NMR (400 MHz, CD₃OD): δ 8.03 (m, 2H), 7.50(d, 1H), 7.42 (s, 1H), 7.20 (m, 2H), 6.02 (m, 1H), 4.22 (s, 2H), 3.96(s, 3H), 3.30 (m, 2H), 2.82-2.40 (m, 7H), 2.13-1.84 (m, 6H). Massspectrum (ESI, m/z): Calcd. for C₂₆H₂₉N₇O, 456.2 (M+H), found 456.2.

EXAMPLE 244-4[(4Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid amide

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (51 mg, 0.10mmol) (as prepared in Example 14, step (b)), NEt₃ (22 μL, 0.15 mmol),trimethylsilyl isocyanate (16 μL, 0.11 mmol) and 1.0 mL of DCM andstirred for 10 h at 25° C. The solvent was evaporated and the titlecompound was purified by RP-HPLC (C18), eluting with 35-60% CH₃CN in0.1% TFA/H₂O over 11 min to give 30 mg (70%) of a white solid. ¹H-NMR(400 MHz, DMSO-d₆): δ 14.28 (br s, 1H), 9.76 (s, 1H), 8.34 (s, 1H), 7.84(d, 1H), 7.18 (dd, 1H), 7.08 (d, 1H), 6.00 (br s, 2H), 5.72 (m, 1H),4.18 (m, 2H), 2.80-2.60 (m, 3H), 2.24-2.10 (m, 4H), 1.80-1.60 (m, 6H),1.50 (m, 2H). Mass spectrum (ESI, mnz): Calcd. for C₂₃H₂₆N₆O, 419.2(M+H), found 419.0.

EXAMPLE 25 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (75 mg, 0.15mmol) (as prepared in Example 14, step (b)), K₂CO₃ (84 mg, 0.60 mmol),2-fluoropyridine (27 μL, 0.30 mmol) and 0.3 mL of N,N-dimethylacetamideand stirred for 8 h at 120° C. The reaction was diluted with 3 mL of H₂Oand the title compound was purified by RP-HPLC (C18), eluting with30-50% CH₃CN in 0.1% TFA/H₂O over 9 min to give 50 mg (75%) of a whitesolid. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.06 (m, 1H), 8.02 (s,1H), 7.94 (dd, 1H), 7.48 (d, 2H), 7.22 (dd, 1H), 7.12 (d, 1H), 6.98 (t,1H), 5.82 (m, 1H), 4.32 (m, 2H), 3.46 (m, 2H), 3.00 (m, 1H), 2.30 (m,4H), 2.18 (m, 2H), 1.96-1.74 (m, 6H). Mass spectrum (ESI, m/z): Calcd.for C₂₇H₂₈N₆O, 453.2 (M+H), found 453.2.

EXAMPLE 26 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), and hydroxy-acetaldehyde according tothe procedure in Example 21. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H),8.02 (s, 1H), 7.22 (dd, 1H), 7.14 (d, 2H), 5.82 (m, 1H), 3.94 (m, 2H),3.74 (m, 2H), 3.30 (m, 2H), 3.18 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H),2.20-1.98 (m, 4H), 1.96-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₄H₂₉N₅O₂, 420.2 (M+H), found 420.2.

EXAMPLE 27 4-Cyano-1H-imidazole-2-carboxylic acid[4-[1-(2-cyano-ethyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (77 mg, 0.16mmol) (as prepared in Example 14, step (b)), NEt₃ (24 μL, 0.16 mmol),acrylonitrile (12 μL, 0.18 mmol), 0.1 mL MeOH and 1.0 mL of1,2-dichloroethane and stirred for 1 h at 80° C. The reaction wasconcentrated and the title compound was purified by RP-HPLC (C18),eluting with 30-50% CH₃CN in 0.1% TFA/H₂O over 12 min to give 83 mg(95%) of a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.06(m, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 5.82 (m, 1H), 3.76 (m, 2H), 3.60(m, 2H), 3.28 (t, 2H), 3.12 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H),2.18-1.98 (m, 4H), 1.92-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₅H₂₈N₆O, 429.2 (M+H), found 429.2.

EXAMPLE 28 4-Cyano-1H-imidazole-2-carboxylic acid[4-(1-carbamoylmethyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (50 mg, 0.10mmol) (as prepared in Example 14, step (b)), NEt₃ (32 μL, 0.23 mmol),2-bromoacetamide (16 mg, 0.12 mmol), and 0.5 mL of DCM and stirred for 4h at 25° C. The reaction was concentrated and the title compound waspurified by RP-HPLC (C18), eluting with 30-50% CH₃CN in 0.1% TFA/H₂Oover 12 min to give 42 mg (75%) of a white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.28 (br s, 1H), 9.78 (s, 1H), 9.50 (br s, 1H), 8.34 (s,1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.18 (dd, 1H), 7.10 (d,1H), 5.76 (m, 1H), 3.94 (s, 2H), 3.58 (m, 2H), 3.12 (m, 2H), 2.80 (m,1H), 2.20 (m, 4H), 1.98 (m, 4H), 1.80 (m, 4H). Mass spectrum (ESI, m/z):Calcd. for C₂₄H₂₈N₆O₂, 433.2 (M+H), found 433.2.

EXAMPLE 29 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)-piperidin-4-yl]-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (25 mg, 0.05mmol) (as prepared in Example 14, step (b)), pyridin-2-yl-acetic acidhydrochloride (10 mg, 0.06 mmol), EDCI (12 mg, 0.06 mmol), HOBt (8.0 mg,0.06 mmol), DIEA (36 ,uL, 0.20 mmol) and 0.2 mL DMF and stirred at 25°C. for 10 h. The reaction was diluted with 2 mL of H₂O and the titlecompound was purified by RP-HPLC (C18), eluting with 30-50% CH₃CN in0.1% TFA/H₂O over 9 min to give 22 mg (70%) of a white solid. ¹H-NMR(400 MHz, CD₃OD): δ 8.82 (d, 1H), 8.52 (t, 1H), 8.14 (d, 1H), 8.04 (s,1H), 7.96 (m, 3H), 7.20 (dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.68 (m,1H), 4.32 (m, 2H), 4.18 (m, 1H), 3.40 (m, 1H), 2.88 (m, 2H), 2.30 (m,4H), 2.06-1.60 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₀N₆O₂,495.2.2 (M+H), found 495.2.

EXAMPLE 30 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-phenyl]-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using pyridin-3-yl-acetic acid. ¹H-NMR (400 MHz, CD₃OD): δ 8.80 (m,2H), 8.54 (d, 1H), 8.10 (d, 1H), 8.06 (t, 1H), 7.98 (s, 1H), 7.18 (dd,1H), 7.08 (d, 1H), 5.78 (m, 1H), 4.68 (m, 1H), 4.20 (m, 1H), 4.18 (s,2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.28 (m, 4H), 2.06-1.70 (m, 7H), 1.62(m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₀N₆O₂, 495.2 (M+H),found 495.2.

EXAMPLE 31 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using pyridin-4-yl-acetic acid. ¹H-NMR (400 MHz, CD₃OD): δ 8.78 (d,2H), 8.12 (d, 1H), 8.00 (m, 3H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.80 (m,1H), 4.66 (m, 1H), 4.22 (s, 2H), 4.18 (m, 1H), 3.34 (m, 1H), 2.84 (m,2H), 2.24 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI,m/z): Calcd. for C₂₉H₃₀N₆O₂, 495.2 (M+H), found 495.2.

EXAMPLE 32 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-piperidin-4-yl)-phenyl)-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. ¹H-NMR (400 MHz,CD₃OD): δ 8.82 (s, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 7.42 (s, 1H), 7.16(dd, 1H), 7.06 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.12 (m, 1H), 4.04(m, 2H), 3.92 (s, 3H), 3.28 (m, 1H), 2.82 (m, 2H), 2.26 (m, 4H),2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. forC₂₈H₃₁N₇O₂, 498.2 (M+H), found 498.2.

EXAMPLE 33 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-[1-(2-1H-imidazol-4-yl-acetyl)-piperidin-4-yl]-phenyl3-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. ¹H-NMR (400 MHz,CD₃OD): δ 8.88 (s, 1H), 8.12 (d, 1H), 8.02 (s, 1H), 7.44 (s, 1H), 7.20(dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.70 (m, 1H), 4.18 (m, 1H), 4.06(m, 2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.30 (m, 4H), 2.00-1.70 (m, 7H),1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₂₉N₇O₂, 484.2(M+H), found 484.2.

EXAMPLE 34 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amidedi-trifluoroacetic acid salt

a) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid(2-cyclohex-1-enyl-4[]-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl]-amide

A flask was charged with4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (830 mg,1.34 mmol) (as prepared in Example 39, step (a)), K₂CO₃ (600 mg, 4.34mmol), sodium iodide (40 mg, 0.27 mmol), 4-(2-chloro-ethyl)-morpholinehydrochloride (260 mg, 1.40 mmol), and 5.0 mL of N,N-dimethylacetamideand stirred for 8 h at 80° C. The reaction was diluted with EtOAc (50mL) and washed with NaHCO₃ (2×50 mL), brine (50 mL) and concentrated.The title compound was purified by flash chomatography (silica gel, 5%MeOH/DCM) to give 650 mg (78%) of a white solid. Mass spectrum (ESI,m/z): Calcd. for C₃₄H₅₀N₆O₃Si, 619.4 (M+H), found 619.3.

b) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl)-amidetrifluoroacetic acid salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide(650 mg, 1.05 mmol) (as prepared in the previous step) in 10 mL of DCMwas added 0.3 mL of EtOH and 3.0 mL of TFA, and the reaction was allowedto proceed for 2 h at 25° C. The reaction was diluted with 10 mL of EtOHand concentrated. The title compound was purified by RP-HPLC (C18),eluting with 30-50% CH₃CN in 0.1% TFA/H₂O over 9 min to give 600 mg(80%) of a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.04(s, 1H), 7.24 (dd, 1H), 7.14 (d, 1H), 5.84 (m, 1H), 3.84 (m, 4H), 3.76(m, 2H), 3.50 (m, 2H), 3.30-3.10 (m, 4H), 2.92 (m, 5H), 2.30 (m, 4H),2.20-2.00 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₈H₃₆N₆O₂, 489.2, found 489.2.

EXAMPLE 35 4-Cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide

a) Trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester

A solution of tetrahydro-thiopyran-4-one (1.00 g, 8.61 mmol) in 10 ml ofTHF was added to a solution of LDA (2.0 M, 4.52 ml, 9.04 mmol) in 20 mlof THF at −78° C. under Ar. The mixture was warmed to RT and stirred for0.5 h, then cooled to −78° C. again. A solution ofN-phenyltrifluoromethanesulfonimide (3.42 g, 9.47 mmol) in 10 ml of THFwas added. The resulting mixture was warmed to RT and stirred for 0.5 hunder Ar. Treated with 200 ml of EtOAc, the mixture was washed with H₂O(3×50 mL), brine (50 mL) and dried (Na₂SO₄). Removal of the solventunder reduced pressure followed by flash chromatography of the residueon silica gel (hexane-3% EtOAc/hexane) gave 810 mg (38%) of the titlecompound as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.01 (m, 1H),3.30 (m, 2H), 2.86 (dd, 2H, J=5.7, 5.7 Hz), 2.58-2.64 (m, 2H). Massspectrum (ESI, m/z): Calcd. for C₆H₇F₃O₃S₂, 249.0 (M+H), found 249.3.

b) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-thiopyran

To a mixture of 4-nitrophenylboronic acid (418 mg, 2.50 mmol),trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (asprepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh₃)₄ (433 mg,0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of1,4-dioxane was added 2.0 M aq Na₂CO₃ solution (3.13 mL, 6.25 mmol). Theresulting mixture was stirred at 80° C. for 2 h and then cooled to RT.Treated with 200 mL of EtOAc, the mixture was washed with H₂O (2×30 mL),brine (30 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(1-3% EtOAc/hexane) gave 470 mg (85%) of the title compound as a lightbrown oil. ¹H-NMR (CDCl₃; 400 MHz): δ 8.19 (d, 2H, J=9.1 Hz), 7.48 (d,2H, J=9.1 Hz), 6.36 (m, 1H), 3.39 (m, 2H), 2.91 (t, 2H, J=5.7 Hz), 2.72(m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₁NO₂S, 222.1 (M+H),found 222.3.

c) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide

A solution of 3-chloroperoxybenzoic acid (1.04 g, 4.62 mmol, 77%) in 15mL of dichloromethane (DCM) was added slowly to a solution of4-(4-nitro-phenyl)-3,6-dihydro-2H-thiopyran (as prepared in the previousstep, 465 mg, 2.10 mmol) in 15 mL of DCM at −78° C. under Ar. Themixture was stirred at −78° C. for 0.5 h, and then warmed to RT. Treatedwith 100 mL of EtOAc, the mixture was washed with 10% Na₂SO₃ (2×15 mL),satd aq NaHCO₃ solution (20 mL), H₂O (20 mL), brine (20 mL) and dried(Na₂SO₄). Removal of the solvent under reduced pressure followed byflash chromatography of the residue on silica gel (2-5% EtOAc/DCM) gave518 mg (97%) of the title compound as a white solid. ¹H-NMR (CDCl₃; 400MHz): δ 8.23 (d, 2H, J=9.0 Hz), 7.52 (d, 2H, J=9.0 Hz), 6.04 (m, 1H),3.86 (m, 2H), 3.26-3.31 (m, 2H), 3.18-3.23 (m, 2H).

d) 4-(1,1-Dioxo-hexahydro-1-thiopyran-4-yl)-phenylamine

A mixture of 4-(4-nitro-phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (asprepared in the previous step, 502 mg, 1.98 mmol) and 10% Pd/C (250 mg,50 wt %) in 15 mL of MeOH was stirred at RT under H₂ (balloon pressure)for 2 h. The Pd catalyst was removed by filtration on Celite, and thefiltrate was concentrated to give 314 mg (70%) of the title compound asa slightly yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 7.03 (d, 2H, J=8.3Hz), 6.67 (d, 2H, J=8.3 Hz), 3.51-3.79 (br s, 2H), 3.11-3.17 (m, 4H),2.70 (dddd, 1H, J=12.3, 12.3, 2.9, 2.9 Hz), 2.31-2.43 (m, 2H), 2.15-2.23(m, 2H).

e) 2-Bromo-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine

To a suspension of4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine (as prepared inthe previous step, 174 mg, 0.77 mmol) in 20 mL of 3:1 DCM/MeOH at 0° C.was added N-bromosuccinimide (NBS) (137 mg, 0.77 mmol) in 5 mL of DCMunder Ar. The mixture was warmed to RT and stirred for 1 h under Ar.Treated with 100 mL of EtOAc, the mixture was washed with H₂O (2×20 mL),brine (20 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(2-3% EtOAc/DCM) gave 155 mg (66%) of the title compound as a whitesolid. ¹H-NMR (CDCl₃; 400 MHz): δ 7.28 (d, 1H, J=2.0 Hz), 6.97 (dd, 1H,J=8.3, 2.0 Hz), 6.73 (d, 1H, J=8.3 Hz), 4.07 (br s, 2H), 3.09-3.14 (m,4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.3, 3.3 Hz), 2.26-2.39 (m, 2H),2.12-2.21 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₄BrNO₂S,304.0 (M+H), found 304.1.

f)2-Cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1-thiopyran-4-yl)-phenylamine

To a mixture of2-bromo-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine (asprepared in the previous step, 150 mg, 0.493 mmol), cyclohexen-1-ylboronic acid (70 mg, 0.542 mmol) and Pd(PPh₃)₄ (57 mg, 0.0493 mmol) in 5mL of 1,4-dioxane was added 2.0 M aq Na₂CO₃ solution (2.0 mL, 4.0 mmol).The resulting mixture was stirred at 80° C. for 8 h under Ar, and thencooled to RT. Treated with 50 mL of EtOAc, the mixture was washed withH₂O (3×15 mL), brine (20 mL) and dried (Na₂SO₄). Removal of the solventunder reduced pressure followed by flash chromatography of the residueon silica gel (2-5% EtOAc/DCM) gave 130 mg (86%) of the title compoundas a brown solid. ¹H-NMR (CDCl₃; 400 MHz): δ 6.89 (dd, 1H, J=8.4, 2.3Hz), 6.84 (d, 1H, J=2.3 Hz), 6.65 (d, 1H, J=8.4 Hz), 5.74 (m, 1H), 3.74(br s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.1, 3.1Hz), 2.29-2.42 (m, 2H), 2.13-2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.732H). Mass spectrum (ESI, m/z): Calcd. for C₁₇H₂₃NO₂S, 306.1 (M+H), found306.1.

g) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

To a mixture of2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine(as prepared in the previous step, 122 mg, 0.50 mmol), potassium4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate(as prepared in Example 3, step (d), 134 mg, 0.44 mmol) andbromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) (205 mg,0.44 mmol) in 5 mL of DMF was added DIEA (209 μL, 1.20 mmol). Theresulting mixture was stirred at RT for 18 h under Ar, cooled to RT.Treated with 50 mL of EtOAc, the mixture was washed with H₂O (3×10 mL),brine (10 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(1-3% EtOAc/DCM) gave 161 mg (73%) of the title compound as a colorlessoil. ¹H-NMR (CDCl₃; 400 MHz): δ 9.69 (s, 1H), 8.29 (d, 1H, J=8.4 Hz),7.78 (s, 1H), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 7.04 (d, 1H, J=2.2 Hz), 5.95(s, 2H), 5.83 (m, 1H), 3.66 (t, 2H, J=8.2 Hz), 3.11-3.20 (m, 4H), 2.77(dddd, 1H, J=12.1, 12.1, 3.2, 3.2 Hz), 2.35-2.47 (m, 2H), 2.17-2.33 (m,6H), 1.74-1.89 (m, 4H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H). Massspectrum (ESI, m/z): Calcd. for C₂₈H₃₈N₄O₄SSi, 555.2 (M+H), found 555.3.

h) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro- IA⁶-thiopyran-4-yl)-phenyl]-amide (as prepared in the previous step, 145mg, 0.261 mmol) in 6 mL of DCM was added 0.20 mL of EtOH followed by 2mL of TFA. The resulting solution was stirred at RT for 3 h. Removal ofthe solvent under reduced pressure followed by flash chromatography ofthe residue on silica gel (20-25% EtOAc/DCM) gave 83 mg (90%) of thetitle compound as a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 12.34 (s,1H), 9.60 (s, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.75 (s, 1H), 7.30 (dd, 1H,J=8.4, 2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.86 (m, 1H), 3.11-3.23 (m, 4H),2.80 (dddd, 1H, J=12.2, 12.2, 2.8, 2.8 Hz), 2.40-2.57 (m, 2H), 2.17-2.35(m, 6H), 1.74-1.91 (m, 4H). Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₄N₄O₃S, 425.2 (M+H), found 425.6.

EXAMPLE 36 4-Cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amidetrifluoroacetic acid salt

a) 2-(3,6-Dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane

A mixture of trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-ylester (as prepared in Example 35, step (a), 500 mg, 2.01 mmol),bis(neopentyl glycolato)diboron (478 mg, 2.11 mmol), Pd(dppf)Cl₂ (147mg, 0.20 mmol) and KOAc (592 mg, 6.03 mmol) in 8 mL of 1,4-dioxane wasstirred at 80° C. for 8 h under Ar, and then cooled to RT. Treated with50 mL of EtOAc, the mixture was washed with H₂O (2×10 mL), brine (10 mL)and dried (Na₂SO₄). Removal of the solvent under reduced pressurefollowed by flash chromatography of the residue on silica gel (0-5%EtOAc/DCM) gave 351 mg (82%) of the title compound as a colorless oil.¹H-NMR (CDCl₃; 400 MHz): δ 6.62 (m, 1H), 3.63 (s, 4H), 3.21 (m, 2H),2.68 (t, 2H, J=5.8 Hz), 2.37 (m, 2H), 0.96 (s, 6H). Mass spectrum (ESI,m/z): Calcd. for C₁₀H₁₇BO₂S, 213.1 (M+H), found 213.1.

b)4-[4-Amino-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (as prepared in Example 13, step (c), 200 mg, 0.563mmol),2-(3,6-dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane (asprepared in the previous step, 131 mg, 0.619 mmol) and Pd(PPh₃)₄ (65 mg,0.056 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na₂CO₃ solution(2.25 mL, 4.5 mmol). The resulting mixture was stirred at 80° C. for 7 hunder Ar, and then cooled to RT. Treated with 50 mL of EtOAc, themixture was washed with H₂O (3×15 mL), brine (20 mL) and dried (Na₂SO₄).Removal of the solvent under reduced pressure followed by flashchromatography of the residue on silica gel (15-30% EtOAc/hexane) gave141 mg (67%) of the title compound as a colorless oil. ¹H-NMR (CDCl₃;400 MHz): δ 6.91 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.65(d, 1H, J=8.2 Hz), 5.91 (m, 1H), 4.22 (br s, 2H), 3.66 (br s, 2H),3.29-3.31 (m, 2H), 2.87 (dd, 2H, J=5.7, 5.7 Hz), 2.77 (m, 2H), 2.47-2.56(m, 3H), 1.78 (d, 2H, J=12.6 Hz), 1.50-1.63 (m, 2H), 1.48 (s, 9H). Massspectrum (ESI, m/z): Calcd. for C₂₁H₃₀N₂O₂S, 375.2 (M+H), found 375.2.

c)4-[4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino)-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of4-[4-amino-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 45 mg, 0.12mmol), potassium4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate(as prepared in Example 3, step (d), 44 mg, 0.144 mmol) and PyBroP (67mg, 0.144 mmol) in 2 mL of DMF was added DIEA (42 μL, 0.24 mmol). Theresulting mixture was stirred at RT for 4 h under Ar. Treated with 30 mLof EtOAc, the mixture was washed with H₂O (3×10 mL), brine (10 mL) anddried (Na₂SO₄). Removal of the solvent under reduced pressure followedby flash chromatography of the residue on silica gel (1-2% EtOAc/DCM)gave 64 mg (85%) of the title compound as a light yellow oil. ¹H-NMR(CDCl₃; 400 MHz): δ 9.51 (s, 1H), 8.21 (d, 1H, J=8.5 Hz), 7.78 (s, 1H),7.16 (dd, 1H, J=8.5, 2.1 Hz), 7.02 (d, 1H, J=2.1 Hz), 6.00 (m, 1H), 5.92(s, 2H), 4.25 (br s, 2H), 3.66 (t, 2H, J=8.2), 3.42 (m, 2H), 2.93 (dd,2H, J=5.7, 5.7 Hz), 2.79 (m, 2H), 2.63 (dddd, 1H, J=12.3, 12.3, 3.3, 3.3Hz), 2.49-2.56 (m, 2H), 1.82(d, 2H, J=12.8 Hz), 1.56-1.66 (m, 2H), 1.49(s, 9H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H).

d)4-[4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of 3-chloroperoxybenzoic acid (91 mg, 0.404 mmol, 77%) in 1mL of DCM was added slowly to4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 120 mg, 0.192mmol) in 3 mL of DCM at −78° C. under Ar. The mixture was stirred at−78° C. for 15 min, and then warmed to RT. Treated with 40 mL of EtOAc,the mixture was washed with 15% Na₂SO₃ (5 mL), satd aq NaHCO₃ solution(2×10 mL), H₂O (10 mL), brine (10 mL) and dried (Na₂SO₄). Removal of thesolvent under reduced pressure followed by flash chromatography of theresidue on silica gel (2-10% EtOAc/DCM) gave 85 mg (67%) of the titlecompound as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 9.23 (s, 1H),8.03 (d, 1H, J=8.3 Hz), 7.80 (s, 1H), 7.21 (dd, 1H, J=8.3, 2.0 Hz), 7.06(d, 1H, J=2.0 Hz), 5.93 (s, 2H), 5.75 (t, 1H, J=4.1Hz), 4.25 (br s, 2H),3.86 (br s, 2H), 3.66 (t, 2H, J=8.2 Hz), 3.29 (t, 2H, J=6.3 Hz), 3.03(t, 2H, J=5.4 Hz), 2.74-2.86 (m, 2H), 2.64 (dddd, 1H, J=12.3, 12.3, 3.3,3.3 Hz), 1.82 (d, 2H, J=12.3 Hz), 1.55-1.65 (m, 2H), 1.49 (s, 9H), 0.98(t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. forC₃₂H₄₅N₅O₆SSi, 656.3 (M+H), found 656.7.

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide,trifluoroacetic acid salt

To a solution of4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 81 mg, 0.123mmol) in 6 mL of DCM was added 0.20 mL of EtOH followed by 2 mL of TFA.The resulting solution was stirred at RT for 3 h. Removal of the solventunder reduced pressure gave 64 mg (96%) of the title compound as a whitesolid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.02 (s, 1H), 7.78 (d, 1H, J=8.3 Hz),7.29 (dd, 1H, J=8.3, 2.0 Hz), 7.21 (d, 1H, J=2.0 Hz), 5.71 (t, 1H, J=4.2Hz), 3.83 (br s, 2H), 3.51 (d, 2H, J=12.4 Hz), 3.33 (t, 2H, J=6.0 Hz),3.15 (td, 2H, J=13.1, 2.6 Hz), 3.01 (m, 2H), 2.94 (dddd, 1H, J=12.2,12.2, 3.5, 3.5 Hz), 2.08 (d, 2H, J=12.9 Hz), 1.91 (m, 2H, J=13.3, 13.3,13.3, 3.8 Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₁H₂₃N₅O₃S, 426.2(M+H), found 426.2.

EXAMPLE 37 4-Cyano-1H-imidazole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid[2-(I1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amidetrifluoroacetic acid salt (as prepared in Example 36, step (e), 62 mg,0.115 mmol) in 4 mL of 1:1 DCM/DMF at RT was added DIEA (60 μL, 0.345mmol). The mixture was stirred for 5 min, then acetic anhydride (11 μL,0.121 mmol) was added slowly to the mixture, and the resulting mixturewas stirred at RT for 0.5 h. Treated with 40 mL of EtOAc, the mixturewas washed with H₂O (2×20 mL). The aqueous layers were extracted withEtOAc (4×10 mL). The combined organic layers were concentrated in vacuo.The residue was purified by flash chromatography on silica gel (1-4%MeOH/DCM) yielding 50.9 mg (95%) of the title compound as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 13.0 (s, 1H), 9.10 (s, 1H), 8.13 (d, 1H,J=8.4 Hz), 7.77 (d, 1H, J=2.3 Hz), 7.26 (dd, 1H, J=8.4, 2.0 Hz), 7.08(d, 1H, J=2.0 Hz), 5.77 (t, 1H, J=4.3 Hz), 4.84 (dt, 1H, J=13.3, 2.1Hz),4.00 (dt, 1H, J=13.3, 2.1 Hz), 3.89 (br s, 2H), 3.31 (t, 2H, J=6.2 Hz),3.23 (td, 1H, J=13.2, 2.5 Hz), 3.02 (m, 2H), 2.77 (dddd, 1H, J=11.9,11.9, 3.4, 3.4 Hz), 2.68 (ddd, 1H, J=12.6, 12.6, 2.9 Hz), 2.18 (s, 3H),1.70-1.97 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₅N₅O₄S,468.2 (M+H), found 468.1.

EXAMPLE 38a 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl]-amide

A mixture of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 655 mg, 1.30 mmol) in DCM (15mL) was cooled to 0° C. and DIEA (0.92 mL, 5.2 mmol) was added.Dimethylaminoacetyl chloride hydrochloride (211 mg, 1.3 mol) was thenadded portion wise over 10 min. The reaction mixture was stirred at 0°C. for 30 min and allowed to warm to RT and stirred for 2 h. Solvent wasremoved in vacuo and the resulting residue was partitioned between brineand DCM. The organic layer was separated, dried (Na₂SO₄) andconcentrated. The residue obtained was purified on silica (5% MeOH: DCM)to obtain 432 mg (70%) of the title compound as a white solid. ¹H-NMR(CDCl₃; 400 MHz): δ 9.49 (s, 1H), 8.24 (d, 1H, J=2.3 Hz), 7.70 (s, 1H),7.12 (dd, 1H, J=8.4, 2.1 Hz), 7.01 (s, 1H), 5.82 (m, 1H), 4.75 (d, 1H,J=13.4Hz), 4.13 (d, 1H, J=13.4 Hz), 3.57 (d, 1H, J=14.2 Hz), 3.18 (d,1H, J=14.2 Hz), 3.12 (td, 1H, J=13.3, 2.4 Hz), 2.73 (dddd, 1H, J=11.9,11.9, 3.8, 3.8 Hz), 2.65 (ddd, 1H, J=13.3, 13.3, 2.4 Hz), 2.40 (s, 6H),2.18-2.32 (m, 4H), 1.60-1.98 (m, 8H). Mass spectrum (ESI, m/z): Calcd.for C₂₆H₃₂N₆O₂, 461.3 (M+H), found 461.2.

EXAMPLE 38b 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl)-amide

HPLC purification of Example 38a also afforded a small amount of4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide.¹H-NMR (CD₃OD; 400 MHz): δ 8.02 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.07(dd, 1H, J=8.4 Hz, J=2.4 Hz), 6.98 (d, 1H, J=2.4 Hz), 5.73-5.68 (m, 1H),4.60-4.51 (m, 1H), 3.76-3.68 (m, 1H), 3.20-3.11 (m, 1H), 2.81-2.70 (m,2H), 2.67 (s, 3H), 2.22-2.13 (m, 4H), 1.88-1.66 (m, 6H), 1.66-1.46 (m,2H). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₀N₆O₂, 447.2 (M+H), found447.3.

EXAMPLE 394-4[(4Cyano-1H-imidazole-2-carbonyl)-aminol-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide

a) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, trifluoroaceticacid salt

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butylester (as prepared in Example 14, step (a), 81 mg, 0.123 mmol) in 18 mLof DCM was added 1 mL of EtOH followed by 5 mL of TFA at 0° C. Theresulting solution was stirred at RT for 0.5 h, treated with 20 mL ofEtOH followed by 20 mL of n-PrOH and 5 mL of H₂O, the mixture was thenconcentrated under reduced pressure to give a slightly yellow solid.Flash chromatography of the compound on silica gel (2-4% MeOH/DCM) gave0.87 g (85%) of the title compound as a white solid. ¹H-NMR (CDCl₃; 400MHz): δ 9.70 (s, 1H), 9.66 (br s, 1H), 9.15 (br s, 1H), 8.29 (d, 1H,J=8.3 Hz), 7.78 (s, 1H), 7.13 (dd, 1H, J=8.3, 2.2 Hz), 7.03 (d, 1H,J=2.2 Hz), 5.95 (s, 2H), 5.83 (m, 1H), 3.66 (t, 2H, J=8.4 Hz), 3.55 (d,2H, J=12.3 Hz), 2.95-3.11 (m, 2H), 2.76 (m, 1H), 2.18-2.33 (m, 4H),1.99-2.15 (m, 4H), 1.82 (m, 4H), 0.97 (t, 2H, J=8.3 Hz), 0.00 (s, 9H).Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₉N₅O₂Si, 506.3 (M+H), found506.1.

b)4-(4-{[4-Cyano-]-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino]-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide

A solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (as prepared in the previous step, 116 mg, 0.192 mmol) andDIEA (134 μL, 0.770 mmol) in 4 mL of DCM was added slowly to solution oftriphosgene (23 mg, 0.0768 mmol) in 4 mL of DCM at −78° C. under Ar. Themixture was stirred at −78° C. for 15 min, warmed to RT and stirred for15 min and cooled to −78° C. again. A suspension of 2-amino-ethanol (350μL, 5.77 mmol) in 4 mL of THF was added and the resulting mixture waswarmed to RT and stirred for 20 h under Ar. Treated with 100 mL ofEtOAc, the mixture was washed with H₂O (3×20 mL), brine (20 mL) anddried (Na₂SO₄). Removal of the solvent in vacuo followed by flashchromatography of the residue on silica gel (10% EtOAc/DCM then 5%MeOH/DCM) gave 95 mg (83%) of the title compound as a colorless oil.¹H-NMR (CDCl₃; 400 MHz): δ 9.68 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 7.77(s, 1H), 7.12 (dd, 1H, J=8.4, 2.2 Hz), 7.01 (d, 1H, J=2.2 Hz), 5.94 (s,2H), 5.83 (m, 1H), 4.96 (t, 1H, J=5.6 Hz), 4.11 (d, 2H, J=13.3 Hz), 3.75(ddd, 2H, J=4.4 Hz), 3.66 (t, 2H, J=8.3 Hz), 3.44 (ddd, 2H, J=5.0 Hz),3.36 (t, 1H, J=4.6 Hz), 2.91 (ddd, 2H, J=13.0, 2.2 Hz), 2.66 (dddd, 1H,J=12.2, 12.2, 3.3, 3.3 Hz), 2.18-2.33 (m, 4H), 1.75-1.91 (m, 6H), 1.67(dddd, 2H, J=12.9, 12.9, 12.9, 4.0 Hz ), 0.97 (t, 2H, J=8.3 Hz), 0.00(s, 9H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₄₄N₆O₄Si, 593.3 (M+H),found 593.1.

c)4-4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide (as prepared in the previous step, 95 mg,0.16 mmol) in 3 mL of DCM was added 0.10 mL of EtOH followed by 1.0 mLof TFA. The resulting solution was stirred at RT for 6 h. Removal of thesolvent under reduced pressure followed by flash chromatography of theresidue on silica gel (2-8% MeOH/DCM) gave 68 mg (92%) of the titlecompound as a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.09 (d, 1H, J=8.4Hz), 8.00 (s, 1H), 7.15 (dd, 1H, J=8.4, 2.2 Hz), 5.79 (m, 1H), 4.15 (dd,2H, J=13.3, 1.1 Hz), 3.61 (t, 2H, J=5.9 Hz), 3.27-3.32 (m, 2H), 2.90(ddd, 2H, J=13.0, 13.0, 2.5 Hz), 2.73 (dddd, 1H, J=12.1, 12.1, 2.6, 2.6Hz), 2.26 (m, 4H), 1.73-1.88 (m, 6H), 1.62 (dddd, 2H, J=12.6, 12.6,12.6, 4.0 Hz ). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₀N₆O₃, 463.2(M+H), found 463.2.

EXAMPLE 40 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl)-amide

a) Methanesulfonic acid 2-methanesulfonyl-ethyl ester

To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mLof DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol)in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. Themixture was warmed to RT and stirred for 20 h under Ar. The mixture wastreated with 100 mL of EtOAc and washed with H₂O (3×20 mL), brine (20mL) and dried (Na₂SO₄). Removal of the solvent in vacuo gave 534 mg(66%) of the title compound as a brown oil. ¹H-NMR (CDCl₃; 400 MHz): δ4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s,3H).

b) 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl)-amide

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 85 mg, 0.174 mmol) and DIEA(91 μL, 0.521 mmol) in 3 mL of DCM at RT was added 2-methanesulfonicacid 2-methanesulfonyl-ethyl ester (as prepared in the previous step, 42mg, 0.208 mmol). The resulting mixture was stirred at RT for 3 h.Treated with 50 mL of EtOAc, the mixture was washed with H₂O (2×20 mL),brine (10 mL) and dried (Na₂SO₄). Removal of the solvent in vacuofollowed by flash chromatography of the residue on silica gel (1-3%MeOH/DCM) gave 54 mg (65%) of the title compound as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 9.54 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 7.72(s, 1H), 7.15 (dd, 1H, J=8.4, 2.0 Hz), 7.04 (d, 1H, J=2.0 Hz), 5.85 (m,1H), 3.21 (t, 1H, J=6.5 Hz), 3.09 (s, 3H), 3.02-3.11 (m, 2H), 2.92 (t,2H, J=6.5 Hz), 2.52 (dddd, 1H, J=12.1, 12.1, 3.3, 3.3 Hz), 2.18-2.34 (m,4H), 2.18 (t, 2H, J=10.8 Hz), 1.64-1.94 (m, 8H). Mass spectrum (ESI,m/z): Calcd. for C₂₅H₃₁N₅O₃S, 482.2 (M+H), found 482.2.

The following compounds have been prepared according to the examples asindicated: Mass Spectrum Example Structure [M + H]⁺ Calcd. Found FormulaProc. Of Ex 41

497.2 497.2 C₂₈H₂₈N₆O₃ 29 42

497.2 497.3 C₂₈H₂₈N₆O₃ 29

EXAMPLE 43 4-Cyano-1H-imidazole-2-carboxylicacid(2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide

A solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 75.0 mg, 0.15 mmol) in CH₂Cl₂(10 mL) was treated with Et₃N (64.1 μL, 0.46 mmol) and cooled to 0° C.The mixture was treated with nicotinoyl chloride hydrochloride (0.030 g,0.17 mmol) and stirred at 0° C. for 15 min then at room temperature for17 h. The reaction mixture was adsorbed directly onto silica gel. Silicagel chromatography (10% MeOH in EtOAc) afforded the title compound (61.0mg, 83%) as a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 9.51 (br s, 1H),8.77 (s, 1H), 8.70-8.66 (m, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.86-7.81 (m,1H), 7.70 (s, 1H), 7.42-7.37 (m, 1H), 7.17 (d, 1H, J=8.4 Hz), 7.06-7.04(m, 1H), 5.87-5.82 (m, 1H), 4.98-4.87 (m, 1H), 3.94-3.84 (m, 1H),3.29-3.18 (m, 1H), 2.98-2.86 (m, 1H), 2.86-2.76 (m, 1H), 2.34-2.20 (m,4H), 1.94-1.72 (m, 9H). LC-MS (ESI, m/z): Calcd. for C₂₈H₂₈N₆O₂, 481.2(M+H), found 481.3.

EXAMPLE 44 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amidetrifluoroacetic acid salt

a)[2-(4-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester

A solution of N-BOC-glycine (0.29 g, 1.63 mmol) in CH₂Cl₂ (10 mL) wastreated with DIEA (0.85 mL, 4.90 mmol), HOBt (0.26 g, 1.96 mmol), andEDCI (0.38 g, 1.96 mmol). The mixture was stirred at room temperaturefor 10 min and added to a suspension of4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 0.80 g, 1.63 mmol) in CH₂Cl₂(20 mL). The solution was stirred at room temperature for 17 h. Solventswere evaporated in vacuo. Silica gel chromatography (50% EtOAc inhexanes) afforded the title compound (0.41 g, 47%) as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 9.53 (s, 1H), 8.26 (d, 1H, J=8.4 Hz),7.80-7.78 (m, 1H), 7.71 (s, 1H), 7.45-7.43 (m, 1H), 7.06 (d, 1H, J=8.4Hz), 7.00 (s, 1H), 5.83 (br s, 1H), 5.76 (br s, 1H), 4.78-4.68 (m, 1H),3.96-3.85 (m, 2H), 3.17-3.03 (m, 1H), 2.78-2.63 (m, 2H), 2.29 (br s,2H), 2.22 (br s, 2H), 1.95-1.87 (m, 2H), 1.86-1.72 (m, 4H), 1.70-1.55(m, 2H), 1.44 (s, 9H). LC-MS (ESI, m/z): Calcd. for C₂₉H₃₆N₆O₄ 533.3(M+H), found 532.9.

b) 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt

A solution of[2-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester (as prepared in the previous step, 0.41 g, 0.77mmol) in CH₂Cl₂ (20 mL) was treated with EtOH (0.2 mL) and TFA (6 mL).The mixture stirred at room temperature for 45 min, and the solventswere evaporated in vacuo. The crude material was used directly in thenext step. LC-MS (ESI, m/z): Calcd. for C₂₄H₂₈N₆O₂ 433.2 (M+H), found433.2.

c) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl3-phenyl)-amidetrifluoroacetic acid salt

A suspension of 4-cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt (as prepared in the previous step, 0.42 g,0.77 mmol) in CH₂Cl₂ (20 mL) was treated with Na(OAc)₃BH (0.33 g, 1.54mmol) and solid glyoxal (44.6 mg, 0.77 mmol). The mixture stirred atroom temperature for 1 h, and the solvent was evaporated in vacuo. Theresidue was taken up in MeOH and the solids filtered off, and thefiltrate was concentrated in vacuo. Reverse phase HPLC (C-18 column)(20% to 60% acetonitrile in water with 0.1% TFA over 30 min) affordedthe title compound (83 mg, 19% over two steps) as a white solid. ¹H-NMR(CD₃OD; 400 MHz): δ 8.16-8.09 (m, 1H), 8.05-8.01 (m, 1H), 7.22-7.15 (m,1H), 7.11-7.06 (m, 1H), 5.84-5.79 (m, 1H), 4.72-4.62 (m, 1H), 4.24-3.91(m, 2H), 3.89-3.80 (m, 2H), 3.28-3.18 (m, 2H), 2.92-2.79 (m, 2H), 2.28(br s, 4H), 1.98-1.89 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.57 (m, 2H).LC-MS (ESI, m/z): Calcd. for C₂₆H₃₂N₆O₃ 477.2 (M+H), found 477.2.

EXAMPLE 45 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethyl)-methyl-amino-acetyl]-piperidin-4-yl)-phenyl)-amidetrifluoroacetic acid salt

A solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amidetrifluoroacetic acid salt (as prepared in Example 44, step (c), 50.0 mg,0.085 mmol) in MeOH (3 mL) was treated with Na(OAc)₃BH (39.5 mg, 0.19mmol) and 37% aqueous formaldehyde (8.2 μL, 0.10 mmol). The mixture wasstirred at room temperature for 5.5 h, and the solvents were removed invacuo. Reverse phase HPLC (C-18 column) (10% to 50% acetonitrile inwater with 0.1% TFA over 30 min) afforded the title compound (19.5 mg,47%) as a white solid. H-NMR (CD₃OD; 400 MHz): δ 8.12 (d, 1H, J=8.4 Hz),8.02 (s, 1H), 7.19 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz),5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m,1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 4H),2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m, 2H). LC-MS (ESI,m/z): Calcd. for C₂₇H₃₄N₆O₃ 491.3 (M+H), found 491.2.

EXAMPLE 46 4-Cyano-1H-imidazole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amidetrifluoroacetic acid salt

a) 5-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of LDA (23.4 mL, 35.1 mmol, 1.5 M in cyclohex) in THF (50 mL)was cooled to −78° C. under Ar. The solution was treated with3-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 25.1 mmol)as a solution in THF (15 mL) via drop wise addition and stirred for 15min. The mixture was treated with1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonimide(12.5 g, 35.1 mmol) as a solution in THF (40 mL). The mixture wasallowed to warm to room temperature and stir 2.5 h. The reaction wasquenched with saturated aqueous NaHCO₃, diluted with Et₂O, and washedwith water. The organic layer was dried over MgSO₄ and concentrated invacuo. Silica gel chromatography (5% EtOAc in hexanes) afforded thetitle compound (2.45 g, 30%) as a colorless oil. ¹H-NMR (CDCl₃; 400MHz): δ 5.97-5.89 (m, 1H), 4.09-4.01 (m, 2H), 3.54-3.45 (m, 2H),2.36-2.26 (m, 2H), 1.48 (s, 9H). LC-MS (ESI, m/z): Calcd. forC₁₁H₁₆F₃NO₅S 332.1 (M+H), found 332.1.

b)5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

PdCl₂dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.07 g,8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomedflask, and the flask was flushed with Ar. A degassed solution of5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol)in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h.The mixture was filtered through a glass-fritted funnel to remove thesolid KOAc, and the filtrate was concentrated in vacuo. Silica gelchromatography (5% EtOAc in hexanes) afforded the title compound (1.62g, 71%) as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.69-6.60 (m,1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s,9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C₁₈H₂₈BNO₄ 310.2 (M+H),found 311.0.

c) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

The title compound was prepared by the Suzuki coupling procedure ofExample 35, step (b) using 4-nitrophenylboronic acid (167 mg, 1.00 mmol)and 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in Example 13, step (a), 295 mg, 1.00mmol). Silica gel chromatography (10% EtOAc in hexanes) afforded thetitle compound (273 mg, 90%) as an oil. ¹H-NMR (CDCl₃; 400 MHz): δ 8.19(d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 6.23 (m, 1H), 4.12 (m, 2H),3.66 (m, 2H), 2.54 (m, 2H), 1.49 (s, 9H).

d) 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-ethanone

A solution of 4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 304 mg, 1.00mmol) in a 1:1 mixture of DCM/TFA (10 mL) was stirred at roomtemperature for 3 h and concentrated. The residue was dried in vacuoovernight, was taken up in CH₂Cl₂ (10 mL) and was cooled to 0° C. Tothis solution, Et₃N (280 μL, 2 mmol) was added drop wise, followed byacetic anhydride (102 μL, 1 mmol). The resulting mixture was stirred at0° C. for 1 h and allowed to warm to room temperature. The reactionmixture was washed with brine, and the organic layer was separated,dried and concentrated. The resulting product was reduced to obtain thetitle compound (143 mg, 65%) using a procedure similar to Example 4,step (d). ¹H-NMR (CDCl₃; 400 MHz): δ 6.97 (d, 2H, J=8.4 Hz), 6.64 (d,2H, J=8.4 Hz), 4.75 (m, 1H), 3.93 (m, 1H), 3.13 (m, 3H), 2.66 (m, 2H),2.12 (s, 3H), 1.84 (m, 2H), 1.57 (m, 2H).

e) 1-[4-(4-Amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone

A solution of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanone (asprepared in the previous step, 0.36 g, 1.66 mmol) in CH₂Cl₂ (10 mL) wascooled to −78° C. and treated with NBS (0.28 g, 1.58 mmol) as asuspension in CH₂Cl₂ (4 mL). The reaction was allowed to warm to roomtemperature and stir for 30 min. The reaction was diluted with CH₂Cl₂and washed with saturated aqueous NaHCO₃. The organic layer was driedover MgSO₄ and concentrated in vacuo. The crude material was useddirectly in the next reaction. LC-MS (ESI, m/z): Calcd. for C₁₃H₁₇BrN₂O297.1 (M+H), found 297.1.

f)5-[5-(1-Acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (asprepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1,9 mL) was treated with 2.0 M aqueous Na₂CO₃ (2.7 mL, 5.38 mmol) and wasdegassed with sonication under Ar. The mixture was heated to 80° C.,treated with Pd(PPh₃)₄ (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5h. The reaction was cooled to room temperature, diluted with EtOAc, andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated in vacuo to afford the title compound (0.25 g,93%) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C₂₃H₃₃N₃O₃422.2 (M+Na), found 422.0.

g)5-(5-(1-Acetyl-piperidin-4-yl)-2-{[4-cyano-1-(2-tyimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of5-[5-(1-acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 0.25 g, 0.63mmol) in CH₂Cl₂ was treated with PyBroP (0.44 g, 0.94 mmol) and4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 3, step (d), 0.21 g, 0.69mmol). The resulting slurry was cooled to 0° C. and treated with DIEA(0.33 mL, 1.88 mmol). The ice bath was removed and the mixture stirredat room temperature for 18 h. The reaction was diluted with CH₂Cl₂ andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated in vacuo. Silica gel chromatography (25-45% EtOAcin hexanes then 100% EtOAc) afforded the title compound (399 mg, 98%) asa white solid. LC-MS (ESI, m/z): Calcd. for C₃₄H₄₈N₆O₅Si 649.4 (M+H),found 649.9.

h) 4-Cyano-1H-imizazole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amidetnifluoroacetic acid salt

A solution of5-(5-(1-acetyl-piperidin-4-yl)-2-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 0.40 g, 0.61mmol) in CH₂Cl₂ (20 mL) and EtOH (0.4 mL) was treated with TFA (3 mL).The solution was stirred at room temperature for 0.5 h. The solventswere evaporated in vacuo, and the residue was immediately taken up inEtOH (25 mL) and stored at 5° C. for 11 h. The solution was concentratedin vacuo, and the residue was taken up in CH₂Cl₂ (20 mL) and EtOH (0.4mL) then treated with TFA (6 mL). The reaction was stirred at roomtemperature for 2 h, and the solvents were evaporated in vacuo. Reversephase HPLC (C-18 column) (10 to 80% acetonitrile in water with 0.1% TFAover 30 min) afforded the title compound (56.9 mg, 22%) as a whitesolid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.06 (s, 1H), 7.81 (d, 1H, J=8.4 Hz),7.32 (d, 1H, J=8.4 Hz), 7.22 (s, 1H), 6.10-6.03 (m, 1H), 4.74-4.64 (m,2H), 4.11-4.02 (m, 1H), 3.95 (s, 2H), 3.50-3.37 (m, 2H), 3.29-3.20 (m,1H), 2.93-2.82 (m, 1H), 2.80-2.69 (m, 1H), 2.62-2.53 (m, 2H), 2.16 (s,3H), 1.98-1.84 (m, 2H), 1.78-1.54 (m, 2H). LC-MS (ESI, m/z): Calcd. forC₂₃H₂₆N₆O₂ 419.2 (M+H), found 419.2.

EXAMPLE 47(4-{4[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl)-aceticacid trifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (33 mg, 0.067mmol) (as prepared in Example 14, step (b)), t-butyl bromoacetate (10μL, 0.067 mmol), NEt₃ (20 μL, 0.135 mmol) and 0.25 mL of DCM and stirredfor 10 h at 25° C. The reaction mixture was loaded on a 5 g SPEcartridge (silica) and 23 mg (70%) of(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-aceticacid tert-butyl ester was eluted with 25% EtOAc/DCM. This compound wasdissolved in 1 mL of DCM and 20 μL of EtOH and 1 mL of TFA were addedand the reaction stirred for 3 h at 25° C. The title compound waspurified by RP-HPLC (C18), eluting with 30-50% CH₃CN in 0.1% TFA/H₂Oover 12 min to give 10 mg (40%) of a white solid. ¹H-NMR (400 MHz,CD₃OD): δ 8.16 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.10 (d, 1H), 5.72(m, 1H), 4.04. (s, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 2.90 (m, 1H), 2.29(m, 4H), 2.10 (m, 4H), 1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₄H₂₇N₅O₃, 434.2 (M+H), found 434.2.

EXAMPLE 48 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl)-amidetrifluoroacetic acid salt

a)[3-(4-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-1,1-dimethyl-3-oxo-propyl]-carbamicacid tert-butyl ester

To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 40.0 mg, 0.0818 mmol),3-tert-butoxycarbonylamino-3-methyl-butyric acid (J. Med. Chem., 34(2),633-642, (1991), 21.4 mg, 0.0981 mmol) and PyBroP (55.0 mg, 0.0981 mmol)in dichloroethane (2 mL) was added DIEA (43 μL, 0.25 mmol) and theresulting mixture was stirred at RT for 1 day under Ar. The mixture wasdiluted with EtOAc (30 mL) and washed with H₂O (2×10 mL), brine (10 mL),dried over Na₂SO₄ and then concentrated in vacuo. The residue waspurified by flash chomatography (silica gel, 10-40% EtOAc/hexane) togive 33.0 mg (70%) of the title compound as a colorless oil. Massspectrum (ESI, m/z): Calcd. for C₃₂H₄₂N₆O₄, 575.3 (M+H), found 574.8.

b) 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

To a solution of[3-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-1,1-dimethyl-3-oxo-propyl]-carbamicacid tert-butyl ester (33.0 mg, 0.0574 mmol) (as prepared in theprevious step) in 3 mL of DCM and 0.10 mL EtOH at 0° C. was added 1.0 mLof TFA, the mixture was warmed to RT and stirred for 3 h. The reactionwas diluted with 3 mL of n-PrOH and then concentrated in vacuo. Theresidue was purified by flash chomatography (silica gel, 3-8% MeOH/DCM)to give 33.5 mg (99%) of the title compound as a white solid. ¹H-NMR(400 MHz, CDCl₃): δ 13.3 (s, 1H), 9.52 (s, 1H), 8.57 (br s, 3H), 8.26(d, 1H, J=8.6 Hz), 7.69 (s, 1H), 7.02 (dd, 1H, J=8.6, 1.7 Hz), 6.98 (d,1H, J=1.7 Hz), 5.78 (m, 1H), 4.67 (br d, 1H, J=13.4 Hz), 3.88 (br d, 1H,J=13.4 Hz), 3.10 (m, 1H), 2.55-2.85 (m, 4H), 2.23 (m, 4H), 1.72-2.01 (m,8H), 1.50 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₃₄N₆O₂,475.3 (M+H), found 475.1.

EXAMPLE 49 4H-[1,2,4]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroaceticacid salt

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester

To a suspension of NaH (60% dispersion) (200 mg, 5.00 mmol) in DMF (5mL) at 0° C., a solution of methyl-1H-1,2,4-triazolecarboxylate (635 mg,5.00 mmol) in DMF (5 mL) was added dropwise. The resulting suspensionwas stirred at the same temperature for 30 min and treated with SEMCl(0.90 mL, 5.0 mmol). The resulting solution was stirred at RT for 30 minand poured onto ice. The product was extracted with ether (3×20 mL). Theether layers were combined, dried (Na₂SO₄) and concentrated in vacuo.The residue obtained was chromatographed on silica (10% EtOAc/hexane) toobtain the title compound (530 mg, 41%). Mass spectrum (ESI, m/z):Calcd. for C₁₀H₁₉N₃O₃Si, 258.1 (M+H), found 258.2.

b)4-(3-Cyclohex-1-enyl-4-{]-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4-]triazole-3-carbonyl]-amino]-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester (as prepared in the previous step, 257 mg, 1.00 mmol)in EtOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resultingsolution was stirred at RT for 20 min and concentrated in vacuo. Theresidue obtained was suspended in ether (10 mL) and sonicated for 5 min.The ether was then removed in vacuo and the resulting residue was driedfor 4 hr to obtain1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid potassium salt (273 mg, 97%) which was directly used in the nextstep without any further purification.

A mixture of1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid potassium salt (as prepared above, 28 mg, 0.10 mmol), DIEA (34 μL,0.20 mmol), 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in Example 14, step (b), 35.6 mg,0.100 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirredat RT for 12 h. The reaction mixture was diluted with DCM (5 mL) andwashed with saturated aqueous NaHCO₃ (10 mL) and water (10 mL). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuoThe product was chromatographed on silica (20-40% EtOAc/hexane) toobtain the title compound (31.9 mg, 55%). Mass psectrum (ESI, m/z):Calcd. for C₁₃H₄₇N₅O₄Si, 481.2 (M-BOC+2H), found. 481.2.

c) 4H-[1,2,4-]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroaceticacid salt

To a solution of4-(3-cyclohex-1-enyl-4-{[1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 81.9 mg, 0.140mmol) in DCM (0.4 mL) and EtOH (13 μL), was added TFA (0.13 mL). Theresulting solution was stirred at RT for 3 h and concentrated in vacuo.The residue obtained was dried under vacuum for 1 h, suspended in ether(10 mL) and sonicated for 5 min. The solid formed was collected bysuction filtration to obtain the title compound (56 mg, 68%). ¹H-NMR(CD₃OD; 400 MHz): δ 8.53 (brs, 1H), 8.20 (d, 1H, J=8.4 Hz), 7.21 (dd,1H, J=8.4, 2.1 Hz), 7.11 (d, 1H, J=2.1 Hz), 5.83 (br s, 1H), 3.45 (m,2H), 3.19 (m, 2H), 2.98 (m, 1H), 2.28 (m, 4H), 2.14 (m, 2H), and1.95-1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C₂₀H₂₅N₅O, 352.4(M+H), found 352.2.

EXAMPLE 50 5-Chloro-4H-[1,2,4]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

a)5-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester

To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5mL) at 0° C., a solution of 5-chloro-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester (Bull. Pharm. Sci., 20(1): 47-61, (1997), 218 mg, 1.35mmol) in DMF (10 mL) was added dropwise. The resulting suspension wasstirred at the same temperature for 30 min and then treated with SEMCl(0.24 mL, 1.4 mmol). The resulting solution was stirred at RT for 30 minand poured onto ice. The mixture was extracted with ether (3×20 mL) andthe ether layers were combined, dried (Na₂SO₄) and concentrated invacuo. The residue obtained was chromatographed on silica (10%EtOAc/hexane) to obtain the title compound (227 mg, 58%). Mass spectrum(ESI, m/z): Calcd. for C₁₀H₁₈ClN₃O₃Si, 292.0 and 294.0 (M+H), found291.5 and 293.6.

b)4-(4-{[5-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino)-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylicacid methyl ester (as prepared in the previous step, 227 mg, 0.780 mmol)in EtOH (2 mL), 2 N KOH (0.4 mL, 0.8 mmol) was added. The resultingsolution was stirred at RT for 20 min and concentrated in vacuo. Theresidue obtained was suspended in ether (10 mL) and sonicated for 5 min.The ether was then removed and the resulting residue was dried in vacuofor 4 h to obtain4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylicacid potassium salt (223 mg, 91%) which was directly used in the nextstep without any further purification.

A mixture of4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid potassium salt (as prepared above, 35 mg, 0.10 mmol), DIEA (34 μL,0.10 mmol), 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in Example 14, step (b), 35.6 mg,0.100 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirredat RT for 12 h. The reaction mixture was diluted with DCM (5 mL) andwashed with saturated aqueous NaHCO₃ (10 mL) and water (10 mL). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuoThe product was chromatographed on silica (20-40% EtOAc/hexane) toobtain the title compound (52 mg, 85%). ¹H-NMR (CDCl₃; 400 MHz): δ 9.60(s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.18 (dd, 1H, J=8.4, 2.2 Hz), 7.13 (d,1H, J=2.2 Hz), 5.99 (s, 2H), 5.84 (br s, 1H), 4.18-4.25 (m, 2H),3.72-3.76 (m, 2H), 2.58-2.67 (m, 2H), 2.51-2.64 (m, 1H), 2.18-2.33 (m,4H), 1.78-1.92 (m, 6H), 1.55-1.65 (m, 2H), 1.49 (s, 9H), 0.93-0.98 (m,2H), 0.10 (s, 9H).

c) 5-Chloro-1H-[1,2,4-]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

To a solution of4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 63.3 mg, 0.102mmol) in DCM (0.5 mL) and EtOH (11 μL) was added TFA (0.1 mL). Afterstirring the resulting mixture at RT for 12 h, another 0.1 mL of TFA wasadded. The reaction mixture was stirred for an additional 5 h at RT, thesolvents were evaporated, and the title compound was purified by RP-HPLC(C18) eluting with 20-70% CH₃CN in 0.1% TFA/H₂O over 20 min to obtainthe title compound (30 mg, 58%). ¹H-NMR (CD₃OD; 400 MHz): δ 8.14 (d, 1H,J=8.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.13 (d, 1H, J=2.1 Hz), 5.82(br s, 1H), 3.45 (m, 2H), 3.19 (m, 2H), 2.98 (m, 1H), 2.28 (m, 4H), 2.14(m, 2H), and 1.95-1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. forC₂₀H₂₄ClN₅O, 386.1 and 388.1 (M+H), found 386.2 and 388.1.

EXAMPLE 51 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt and 5-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amidebis trifluoroacetic acid salt

a) Cis/trans 2,6-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butylester

A solution of cis/trans-2,6-dimethylpiperidinone (Coll. Czech. Chem.Commun.: 31(11), 4432-41, (1966), 1.27 g, 10.0 mmol) in ether (100 mL)was treated with aq 1 N NaOH (11 mL, 11 mmol) and (BOC)₂O (2.18 g, 10.0mmol). The resulting mixture as stirred at RT for 48 hr. The ether layerwas separated, dried and concentrated. The residue was chromatographedon silica (10% EtOAc-hexane) to obtain the title compound (1.10 g, 50%):LC-MS (ESI, m/z): Calcd. for C₁₂H₂₁NO₃, 128.1 (M-BOC+2H), found 128.1.

b) 4-(4-Amino-phenyl)-cis/trans 2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester

A solution of cis/trans N-Boc-2,6-dimethylpiperidinone (as prepared inthe previous step, 1.14 g, 5.00 mmol) in THF (20 mL) was cooled to −78°C. and treated with LDA (1.5 M solution in cyclohex, THF andethylbenzene, 4.4 mL, 6.5 mmol) under Ar. The resulting mixture wasstirred at the same temperature for 30 min and treated withN-phenyltrifluoromethanesulfonimide (2.34 g, 6.55 mmol) in THF (20 mL).The reaction mixture was stirred for another 30 min and allowed to warmto RT. After 30 min. at RT the reaction mixture was concentrated invacuo and the residue was taken up in ether (20 mL) and washed with coldwater (2×10 mL). The ether layer was dried (Na₂SO₄) and concentrated toaffordedcis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (890 mg, 49%) which was directly used in nextstep.

The title compound was then prepared according to the Suzuki couplingprocedure of Example 35, step (b) using 4-aminophenylboronic acid (219mg, 1.00 mmol) andcis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared above, 321 mg, 1.00 mmol). Silica gelchromatography (10-20% EtOAc/hexanes) afforded4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (172 mg, 57%): Mass spectrum (ESI, m/z): Calcd.for C₁₈H₂₆N₂O₂, 303.2 (M+H) found 303.1.

A solution of4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared above, 380 mg, 1.25 mmol) in MeOH (10mL) was hydrogenated over 10% Pd/C (190 mg) at 20 psi for 1 h. Thesolution was filtered through a pad of Celite and concentrated to givethe title compound (360 mg, 94%). Mass spectrum (ESI, m/z): Calcd. forC₁₈H₂₈N₂O₂, 305.2 (M+H), found 305.6.

c) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-cis/trans2,6-dimethyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-(4-amino-phenyl)-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (as prepared in previous step, 334 mg, 1.09 mmol)in DCM (10 mL) was added NBS (195 mg, 1.09 mmol) and the reactionmixture was stirred at RT for 12 h. The reaction mixture was dilutedwith DCM (10 mL) and washed with saturated aqueous NaHCO₃ (10 mL) andwater (10 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo to obtain4-(4-amino-3-bromo-phenyl)-cis/trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (367 mg, 87%). Mass spectrum (ESI, m/z): Calcd.for C₁₈H₂₇BrN₂O₂, 327.0 and 329.0 (M-t-Bu+H), found 327.0 and 328.9.

The title compound was then prepared according to the Suzuki couplingprocedure of Example 12, step (d) using cyclohexan-1-enyl boronic acid(157 mg, 1.25 mmol) and4-(4-amino-3-bromo-phenyl)-2,6-dimethyl-piperidine-1-carboxylic acidtert-butyl ester (as prepared above, 382 mg, 1.00 mmol) andchromatographed on silica (20% EtOAc/hexanes) to afford 254 mg (66%).Mass spectrum (ESI, m/z): Calcd. for C₂₄H₃₆N₂O₂, 384.2 (M+H), found385.1.

d)4-(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-cis-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester and4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 3, step (d), 384 mg, 1.00mmol), DIEA (0.34 μL, 2.0 mmol),4-(4-amino-3-cyclohex-1-enyl-phenyl)-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 384 mg, 1.00mmol) and PyBroP (699 mg, 1.50 mmol) in DCM (20 mL) was stirred at RTfor 12 h. The reaction mixture was diluted with DCM (10 mL) and washedwith saturated aqueous NaHCO₃ (10 mL) and water (10 mL). The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo toobtained a mixture of the above two title compounds (321 mg, 50.7%). Themixture was chromatographed on silica (10-20% EtOAc/hexane) to obtainthe individual title compounds.

-   4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylic    acid tert-butyl ester (31 mg). Mass spectrum (ESI, m/z): Calcd. for    C₃₅H₅₁N₅O₄Si, 634.3 (M+H), found 634.1.-   4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-cis-2,6-dimethyl-piperidine-1-carboxylic    acid tert-butyl ester contaminated with 10% of    4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylic    acid tert-butyl ester (290 mg). Mass spectrum (ESI, m/z): Calcd. for    C₃₅H₅₁N₅O₄Si, 634.3 (M+H), found 634.1.

e) 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt and 5-cyano-1-H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amidebis trifluoroacetic acid salt

The title compounds were prepared from 290 mg (0.457 mmol) of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-cis-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester and 31 mg (0.048 mmol) of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester according to the procedure in Example 14, step(b).

-   5-Cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide    bis trifluoroacetic acid salt (93 mg, 32%): ¹H-NMR (CD₃OD; 400 MHz):    δ 8.17 (d, 1H, J=8.4 Hz), 8.03 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.11    (s, 1H), 5.72 (br s, 1H), 3.87 (m, 1H), 3.78 (m, 1H), 3.45 (m, 1H),    3.23 (m, 1H), 3.07 (m, 1H), 2.22 (m, 4H), 2.19 (m, 2H), 1.75-1.92    (m, 4H), 1.56 (m, 3H), 1.37 (m, 6H). Mass spectrum, ESI, n/z):    Calcd. for C₂₄H₂₉N₅O, 404.2 (M+H), found 404.2.-   5-Cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide    bis trifluoroacetic acid salt (17.3 mg, 56%). ¹H-NMR (CDCl₃; 400    MHz): δ 13.9 (br s, 1H), 10.3 (br s, 1H), 9.98 (s, 1H), 8.41 (d, 1H,    J=8.4 Hz), 7.75 (br s, 1H), 7.26 (dd, 1H, J=8.4, 2.0 Hz), 7.15 (d,    1H, J=2 Hz), 5.92 (br s, 1H), 4.12 (m, 1H), 3.59 (m, 1H), 3.1-3.3    (m, 4H), 2.25-2.42 (m, 6H), 2.05-1.78 (m, 6H), 1.62 (d, 3H, J=7.1    Hz), 1.43 (d, 3H, J=6.3 Hz). Mass spectrum (ESI, m/z): Calcd. for    C₂₄H₂₉N₅O, 404.2 (M+H), found 404.2.

EXAMPLE 52 5-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl]-amide

a) 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-[1-(R)-(+)2,2-dimethyl-[1,3]dioxolane-4-carbonyl)-piperidin-4-yl]-phenyl}-amide

To a solution of methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate(0.16 mL, 1.0 mmol) in MeOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added.The resulting solution was stirred at RT for 20 min and concentrated invacuo. The residue obtained was suspended in ether (10 mL) and sonicatedfor 5 min. The ether was then removed and the resulting residue wasdried in vacuo for 4 h to obtain(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (173mg, 94%) which was directly used in the next step without purification.

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, trifluoroacetic acidsalt (as prepared in Example 14, step (b), 40 mg, 0.08 mmol) in DCM (1.5mL) was added to a mixture of(R)-(+)-2,2-dimethyl-1,3-dioxalane-4-carboxylic acid potassium salt (asprepared above, 18 mg, 0.090 mmol), EDCI (18.8 mg, 0.0900 mmol), HOBt(13.2 mg, 0.0900 mmol) and DIEA (42 μL, 0.24 mmol). The resultingmixture was stirred at RT for 6 h. Water (10 mL) was added and DCM layerwas separated, dried (Na₂SO₄) and concentrated. The residue obtained waschromatographed on silica (2% MeOH/DCM) to obtain title compound (47 mg,97%). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₃N₅O₄, 504.2 (M+H),found 503.9.

b) 5-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide

To a solution of 5-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(2,2-dimethyl-[1,3]dioxolane-4-carbonyl)-piperidin-4-yl]-phenyl}-amide (as prepared in the previous step, 45mg, 0.090 mmol) in MeOH (1 mL) was added aq 2 N HCl (2 mL). Theresulting mixture was stirred at RT for 12 hr. Solvents were removed invacuo and the resulting residue was dried for 4 h. The ether (10 mL) wasadded and sonicated for 5 min. The ether was removed in vacuo and theresidue was dried for 12 h to obtain the title compound (21.3 mg, 52%).¹H-NMR (DMSO; 400 MHz): δ 14.1 (br s, 1H), 9.85 (s, 1H), 8.32 (s, 1H),7.92 (d, 1H, J=8.4Hz), 7.18 (dd, 1H, J=8.4,2.1 Hz), 7.13 (d, 1H, J=2.1Hz), 5.72 (br s, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 4.15 (m, 1H), 3.55 (m,1H), 3.43 (m, 1H), 3.08 (m, 1H), 2.81 (m, 1H), 2.63 (m, 1H), 2.12-2.24(m, 4H), 1.31-1.38 (m, 10 H). mass spectrum (ESI, m/z): Calcd. forC₂₅H₂₉N₅O₄, 464.2 (M+H), found 464.1.

EXAMPLE 53 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

a) 4-(1-Methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine

A solution of N-methoxypiperidinone (J. Org. Chem., 26, 1867, (1961),650 mg, 5.00 mmol) in THF (20 mL)) was cooled to −78° C. and treatedwith LDA (1.5 M solution in cyclohex, THF and ethylbenzene, 4.3 mL, 6.4mmol) under Ar. The resulting mixture was stirred at same temperaturefor 30 min and treated with N-phenyltrifluoromethanesulfonimide (2.3 g,6.4 mmol) in THF (20 mL). The reaction mixture was stirred for another30 min and allowed to warm to RT. After 30 min at RT, the reactionmixture was concentrated in vacuo and the residue obtained was taken upin EtOAc (20 mL) and washed with cold water (2×10 mL). EtOAc layer wasdried (Na₂SO₄) and concentrated to afforded trifluoromethanesulfonicacid 1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl ester (980 mg , 71%) as awhite foam which was directly used in next step

The title compound was then prepared according to Suzuki couplingprocedure of Example 35, step (b) using 4-aminophenylboronic acid (219mg, 1.00 mmol) and trifluoromethanesulfonic acid1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl ester (as prepared above, 261mg, 1.00 mmol). Silica gel chromatography (20-50% EtOAc/hexanes)afforded 60 mg (29%). Mass spectrum (ESI, m/z): Calcd. for C₁₂H₁₆N₂O,205.1 (M+H), found 205.2.

b) 2-Cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine

A solution of 4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine(as prepared in previous step) (40.8 mg, 0.200 mmol) in MeOH (5 mL) washydrogenated over 10% Pd/C (20.4 mg) at 20 psi for 1 h. The solution wasfiltered through a pad of Celite and concentrated to give4-(1-methoxy-piperidin-4-yl)-phenylamine (38 mg, 92%) which was directlyused in the next step without purification.

To a solution of 4-(I-methoxy-piperidin-4-yl)-phenylamine (as preparedabove, 42 mg, 0.20 mmol) in DCM (2 mL) was added NBS (36.2 mg, 0.20mmol) and the reaction mixture was stirred at RT for 12 h. The reactionmixture was diluted with DCM (10 mL) and washed with saturated aqueousNaHCO₃ (10 mL) and water (10 mL). The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo to obtain2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (43mg, 74.5%) which was used in the next step without purification.

The title compound was then prepared according to Suzuki couplingprocedure of Example 12, step (d) using cyclohex-1-enyl boronic acid(27.9 mg, 1.00 mmol) and2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (asprepared above, 44 mg, 0.15 mmol) and chromatographed on silica (20-50%EtOAc/hexanes) afforded2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (33 mg, 74%).Mass spectrum, (ESI, m/z): Calcd. for C₁₈H₂₆N₂O, 287.2 (M+H), found286.8.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide

A mixture of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 3, step (d), 35.6 mg, 0.100mmol), DIEA (0.34 μL, 0.20 mmol),2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (as preparedin previous step, 28.6 mg, 0.1 mmol) and PyBroP (69.9 mg, 0.150 mmol) inDCM (2 mL) was stirred at RT for 12 h. The reaction mixture was dilutedwith DCM (10 mL) and washed with saturated aqueous NaHCO₃ (10 mL) andwater (10 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo The product was chromatographed on silica (20-40%EtOAc/hexane) to obtain the title compound (26 mg, 48%). Mass spectrum(ESI, m/z): Calcd. for C₂₉H41N₅O₃Si, 536.3 (M+H), found 536.2.

d) 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide (asprepared in previous step, 31 mg, 0.020 mmol) in DCM (0.5 mL) and EtOH(11 μL) was added TFA (0.1 mL). The resulting solution was stirred at RTfor 6 h. The reaction mixture was concentrated in vacuo and theresulting residue was dried for 1 h, suspended in ether (10 mL) andsonicated for 5 min. The solid formed was collected by suctionfiltration to obtain the title compound (17.3 mg, 58%). 1H-NMR (DMSO;400 MHz): δ 9.70 (s, 1H), 8.30 (s, 1H), 7.83 (d, 1H, J=8.4 Hz), 7.14 (d,1H, J=8.4 Hz), 7.05 (s, 1H), 5.71 (br s, 1H), 3.30-3.55 (m, 5H),2.41-2.62 (m, 2H), 2.12-2.19 (m, 4H), 1.60-1.85 (m, 8H). Mass spectrum(ESI, m/z): Calcd. for C₂₃H₂₇N₅O₂, 406.2 (M+H), found 406.1.

EXAMPLE 54 4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

a) 5-Nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

A solution of 202 mg (0.994 mmol) 2-bromo-5-nitropyridine in 4 mL oftoluene and 2 mL of EtOH was treated with 338 mg (1.09 mmol)4-trifluoromethane-sulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (Synthesis, 993, (1991)) and 1.49 mL (2.981 mmol) 2 Maqueous Na₂CO₃. The mixture was degassed via sonication, placed underargon, treated with 80.3 mg (0.00700 mmol) Pd(PPh₃)₄ and heated to 80°C. for 4 h. The mixture was diluted with EtOAc and washed with water.The organic layer was dried over MgSO₄ and concentrated in vacuo. Theresulting residue was chromatographed on a 50-g silica Varian MegaBondElut column with 10-25% EtOAc-hexane to afford 226 mg (75%) of the titlecompound as a light yellow solid: Mass spectrum (ESI, m/z): Calcd. forC₁₅H₁₉N₃O₄, 306.1 (M+H), found 305.7.

b) 5-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 226 mg (0.740 mmol)5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (as prepared in the previous step) in 15 mL MeOH wastreated with 110 mg 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% byweight water) and 1 atm H₂ at room temperature for 18 h. The mixture wasfiltered through Celite, and the filter cake was washed with MeOH.Concentration afforded 220 mg (107%) of the title compound as acolorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C₁₅H₂₃N₃O₂,278.2 (M+H), found 278.0.

c)5-Amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxlicacid tert-butyl ester

A solution of 220 mg (0.793 mmol)5-amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (as prepared in the previous step) in 10 mL CH₂Cl₂ wastreated with 134 mg (0.753 mmol) N-bromosuccinimide at room temperaturefor 20 min. The mixture was diluted with CH₂Cl₂ and washed withsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated in vacuo. Chromatography of the residue on a 50-g silicaVarian MegaBond Elut column with 10-35% EtOAc-hexanes afforded 209 mg(74%) of the title compound as a colorless gliassy solid. ¹H-NMR (CDCl₃;400 MHz): δ 6.97 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=8.0 Hz), 4.28-4.15(br s, 2H), 4.06-3.90 (m, 2H), 2.85-2.75 (m, 2H), 2.77-2.68 (m, 1H),192-1.83 (m, 2H), 1.68-1.54 (m, 2H), 1.47 (s, 9H).

d)5-Amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 209 mg (0.587 mmol)5-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (as prepared in the previous step) in 5 mL oftoluene and 2.5 mL of EtOH was treated with 99.3 mg (0.645 mmol)4,4-dicyclohex-1-enylboronic acid and 2.34 mL (4.69 mmol) 2 M aqueousNa₂CO₃. The mixture was degassed via sonication, placed under argon,treated with 47.4 mg (0.0410 mmol) Pd(PPh₃)₄, and heated to 80° C. for16 h. The mixture was diluted with EtOAc and washed with water. Theaqueous layer was extracted with additional EtOAc, and the combinedorganic layers were dried over MgSO₄ and concentrated in vacuo.Chromatography of the residue on a 50-g silica Varian MegaBond Elutcolumn with 25% EtOAc-hexanes afforded 150 mg (66%) of the titlecompound as a white foamy solid. Mass spectrum (ESI, m/z): Calcd. forC₂₃H₃₅N₃O₂, 386.3 (M+H), found 386.3.

e)5-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 150 mg (0.389 mmol)5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (as prepared in the previous step) in 15 mL ofCH₂Cl₂ was treated with 131 mg (0.428 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (b)), 272 mg (0.584 mmol)PyBroP, and 203 μL (1.17 mmol) DIEA at room temperature for 3 h. Themixture was diluted with CH₂Cl₂ and washed with saturated aqueousNaHCO₃. The organic layer was dried over MgSO₄ and concentrated invacuo. Chromatography of the residue on a 50-g silica Varian MegaBondElut column with 50% EtOAc-hexanes afforded 215 mg (87%) of the titlecompound as a white solid. Mass spectrum (ESI, m/z): Calcd. forC₃₄H₅₀N₆O₄Si, 635.4 (M+H), found 635.3.

f) 4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

A solution of 215 mg (0.339 mmol)5-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (as prepared in the previous step) in 10 mL ofCH₂Cl₂ was treated with three drops MeOH and 3 mL TFA at roomtemperature for 4 h. MeOH (10 mL) was added and the solvents evaporatedin vacuo. Chromatography of the residue on a 50-g silica Varian MegaBondElut column with 10% MeOH—CH₂Cl₂ afforded 210 mg (97%) of the titlecompound as a white solid.

¹H-NMR (CD₃OD; 400 MHz): δ 8.59 (d, 1H, J=8.4 Hz), 8.04 (s, 1H), 7.28(d, 1H, J=8.4 Hz), 6.02-5.93 (m, 1H), 3.58-3.48 (m, 2H), 3.32-3.03 (m,3H), 2.54-2.42 (m, 2H), 2.23-2.02 (m, 6H), 1.11 (s, 6H). Mass spectrum(ESI, m/z): Calcd. for C₂₃H₂₈N₆O, 405.2 (M+H), found 405.2.

EXAMPLE 55 4-Cyano-1H-imidazole-2-carboxylic acid[1′-(2-dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

A suspension of 20.9 mg (0.203 mmol) N,N-dimethylglycine in 4 mL CH₂Cl₂was treated with 49.8 mg (0.197 mmol)bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl) and 75 μL (0.54mmol) Et₃N at room temperature for 1 h. The mixture was then treatedwith 70.0 mg (0.135 mmol) 4-cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetate (as prepared in Example 54, step(f)) at roomtemperature for 18 h. The mixture was diluted with CH₂Cl₂ and washedwith water. The organic layer was dried over MgSO₄ and concentrated invacuo. The residue was purified by RP-HPLC (C1 8) with 10-80% CH₃CN in0.1% TFA/H₂O over 30 min to afford 34.9 mg (53%) of the title compoundas a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.38 (d, 1H, J=8.4 Hz),8.05 (s, 1H), 7.33 (d, 1H, J=8.4 Hz), 6.05-5.98 (m, 1H), 4.68 (d, 1H,J=15.2 Hz), 3.82 (d, 1H, J=15.2 Hz) 3.16-3.05 (m, 1H), 3.01-2.94 (m,6H), 2.52-2.40 (m, 2H), 2.39 (s, 6H), 2.10 (m, 2H), 2.09-1.87 (m, 2H),1.67-1.59 (m, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z): Calcd. forC₂₇H₃₅N₇O₂, 490.3 (M+H), found 490.4.

EXAMPLE 56 4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

A solution of 70.0 mg (0.135 mmol) 4-cyano-1H-imidazole-2-carboxylicacid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide(as prepared in Example 54, step (f)) in 10 mL of CH₂Cl₂ was treatedwith 32.7 mg (0.162 mmol) methanesulfonic acid 2-methanesulfonyl-ethylester (as prepared in Example 40, step (a)) and 70.5 μL (0.405 mmol)DIEA at room temperature for 6 h. The mixture was diluted with CH₂Cl₂and washed with water. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by RP-HPLC (C 18) with20-60% CH₃CN in 0.1% TFA/H₂O over 30 min to afford 48 mg (85%) of thetitle compound as a white solid. H-NMR (CD₃OD; 400 MHz): δ 8.65 (d, 1H,J=8.4 Hz), 8.05 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 6.05-5.98 (m, 1H),3.85-3.66 (m, 6H), 3.29-3.21 (m, 2H), 3.20-3.01 (m, 1H), 3.14 (s, 3H),2.53-2.45 (m, 2H), 2.30-2.15 (m, 4H), 2.15-2.10 (m, 2H), 1.62 (t, 2H,J=6.4 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. forC₂₆H₃₄N₆O₃S, 511.2 (M+H), found 511.3.

EXAMPLE 57 5-Cyano-1H-imidazole-2-carboxylic acid(4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl)-amidetrifluoroacetic acid salt

a){2-[4(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-carbamicacid tert-butyl ester

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (231 mg, 0.380 mmol) (as prepared in Example 14,step (a)) in 2.5 mL of DCM and 0.4 mL EtOH was added 700 μL of TFA andthe solution stirred for 3 h at 25° C. The reaction was diluted with 4mL of EtOH and then concentrated to give ca. a 2:1 mixture of5-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt to starting material by ¹H-NMR and LC/MS which was used in thefollowing step without further purification. The mixture in 3 mL of DCMwas added to a solution of 2-tert-butoxycarbonylamino-2-methyl-propionicacid (53 mg, 0.70 mmol), DIEA (122 μL, 0.700 mmol) and PyBroP (144 mg,0.300 mmol) in 3 mL of DCM and the reaction was stirred at 25° C.overnight. The reaction was diluted with EtOAc (25 mL) and washed withsatd aq NaHCO₃ (1×25 mL) and brine (25 mL) and the organic layer wasdried over Na₂SO₄ and then concentrated. Purification of the residue bypreparative TLC (50% EtOAc-hexanes) afforded 40 mg (15%) of the titlecompound as a white solid. Mass Spectrum (ESI, m/z): Calcd. forC₃₇H₅₅N₆O₅Si, 691.3 (M+H), found 691.1.

b) 5-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

To a solution of{2-[4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-carbamicacid tert-butyl ester (40 mg, 0.050 mmol) in 2 mL of DCM and 20 μL ofEtOH was added 1.5 mL of TFA. The solution was stirred for 3 h at 25°C., diluted with 2 mL of EtOH and concentrated in vacuo. Trituration ofthe residue with ether afforded 8.4 mg (29%) of the title compound as awhite solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.10 (d, 1H, J=8.4 Hz), 8.00 (s,1H), 7.16 (d, 1H, J=8.4 Hz), 7.07 (s, 1H), 5.79 (s, 1H), 4.55-4.48 (m,1H), 3.30 (s, 6H), 2.89-2.87 (m, 2H), 2.40-2.25 (m, 4H), 1.96-1.93 (m,2H), 1.86-1.83 (m, 6H), 1.64-1.61 (m, 2H). Mass Spectrum (ESI, m/z):Calcd. for C₂₆H₃₃N₆O₂, 461.2 (M+H), found 461.3.

EXAMPLE 58 5-Cyano-1H-imidazole-2-carboxylic acid[6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide

a)5-Amino-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

To a mixture of5-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (331 mg, 0.93 mmol) (as prepared in Example 54,step (c)) and cyclohexen-1-yl boronic acid (141 mg, 1.11 mmol) in 5 mLof EtOH, 10 mL of toluene and 5 mL of 2 M Na₂CO₃, was added Pd(PPh₃)₄(107 mg, 0.0930 mmol) and the result was heated at 80° C. for 16 h. Thereaction was diluted with 100 mL of ether and 100 mL of brine and thelayers were separated. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. Purification of the residue by columnchromatography (silica gel, 30-60% ether-hexanes) afforded 248 mg (74%)the title compound as an light brown oil LC-MS (ESI, m/z): Calcd. forC₂₁H₃₂N₃O₂ (M+H), 358.2, found 358.1.

b)5-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (296 mg, 0.970 mmol) (as prepared in Example 3, step (d))in 8 mL DCM was added DIEA (291 μL, 1.72 mmol) and PyBroP (512 mg, 1.10mmol), and the reaction was stirred at 25° C. for 15 min. A solution of5-amino-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (233 mg, 0.65 mmol) (as prepared in the previousstep) in 4 mL DCM was added and the reaction stirred overnight at 25° C.The reaction was diluted with EtOAc (25 mL) and washed with NaHCO₃ (1×25mL) and brine (25 mL) and the organic layer was dried over Na₂SO₄ andthen concentrated. The residue was purified by flash chomatography(silica gel, 5% MeOH-CHCl₃) to afford 167 mg (40%) of the title compoundas a white solid. Mass Spectrum (ESI, m/z): Calcd. for C₃₂H₄₆N₆O₄Si,607.3 (M+H), found 607.3.

c) 5-Cyano-1H-imidazole-2-carboxylic acid(6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amidetrifluoroacetic acid salt

The title compound was prepared from5-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (167 mg, 0.27 mmol) using a procedure similar toExample 14, step (b) to afford 57 mg (43%) of the title compound as awhite solid. LC-MS (ESI, m/z): Calcd. for C₂₁H₂₄N₆O, 377.2 (M+H), found377.2.

d) 5-Cyano-1H-imidazole-2-carboxylic acid[6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amide

To a slurry of 5-cyano-1H-imidazole-2-carboxylic acid(6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amidetrifluoroacetic acid salt (57 mg, 0.11 mmol) in 5 mL of DCM was addedDIEA (50.4 μL, 0.290 mmol) followed by 30.5 mg (0.150 mmol) ofmethanesulfonic acid 2-methanesulfonyl-ethyl ester (as prepared inExample 40, step(a)). The reaction was allowed to stir overnight,diluted with 20 mL of DCM, washed with satd aq NaHCO₃ (1×20 mL) anddried over Na₂SO₄. Purification by preparative TLC (silica gel, 40%EtOAc-hexanes) afforded 22.3 mg (40%) of the title compound as a whitesolid. ¹H-NMR (DMSO; 400 MHz): δ 10.02 (s, 1H), 8.24 (s, 1H), 8.11 (d,1H, J=8.4 Hz), 7.18 (d, 1H, J=8.4 Hz), 5.96 (s, 1H), 3.04 (s, 3H),3.02-2.99 (m, 3H), 2.73 (t, 2H, J=2.7 Hz), 2.39-2.37 (m, 2H), 2.11-2.05(m, 4H), 1.85-1.64 (m, 10H). Mass Spectrum (ESI, m/z): Calcd. forC₂₄H₃₁N₆O₃S, 483.2 (M+H), found 483.3.

EXAMPLE 59

An alternate method for the synthesis of the intermediate described inExample 3 is described below.

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

a) 1H-Imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, a condenser, and an addition funnel with anitrogen inlet was charged with 1H-imidazole-4-carboxaldehyde (Aldrich,1.10 kg, 11.5 mol) and pyridine (3.0 L, 3.0 mol). The reaction flask wascooled to 8° C. with an ice bath and hydroxylamine hydrochloride (871 g,12.5 mol) was added slowly in portions to maintain the internaltemperature below 30° C. The reaction was allowed to cool to ambienttemperature and stirred for 2 h at ambient temperature. The resultingthick yellow solution was heated to 80° C. with a heating mantle andacetic anhydride (2.04 L, 21.6 mol) was added dropwise over 200 min tomaintain the temperature below 110° C. during the addition. The reactionmixture was heated at 100° C. for 30 min, after which time it wasallowed to cool to ambient temperature and then further cooled in an icebath. The pH was adjusted to 8.0 (pH meter) by the addition of 25 wt %NaOH (5.5 L) at such a rate that the internal temperature was maintainedbelow 30° C. The reaction mixture was then transferred into a 22-Lseparatory funnel and extracted with ethyl acetate (6.0 L). The combinedorganic layer was washed with brine (2×4.0 L), dried over MgSO₄,filtered, and concentrated to dryness under reduced pressure at 35° C.to give the crude product as a yellow semisolid. The resulting semisolidwas suspended in toluene (3.0 L) and stirred for 1 h, after which timeit was filtered to give a light yellow solid, which was resuspended intoluene (3.0 L) and stirred for 1 h. The resulting slurry was filteredand the filter cake washed with toluene (2×500 mL) to give the titlecompound as a light yellow solid [870 g, 82%). The ¹H and ¹³C NMRspectra were consistent with the assigned structure.

b) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with 1H-imidazole-4-carbonitrile (830 g, 8.91 mol, asprepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol),and acetone (6.0 L). Agitation was initiated and the mixture was cooledto 10° C. with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added throughthe addition funnel over 210 min to maintain the internal temperaturebelow 15° C. The reaction was then allowed to warm to ambienttemperature and stirred at ambient temperature overnight (20 h). Thereaction mixture was then cooled in an ice bath to 10° C. and quenchedby the slow addition of water (8.0 L) over 30 min to maintain theinternal temperature below 30° C. The resulting mixture was transferredto a 22-L separatory funnel and extracted with ethyl acetate (2×7.0 L).The combined organics were concentrated under reduced pressure at 35° C.to give the crude product as a dark brown oil, which was purifiedthrough a plug of silica gel (16.5×20 cm, 2.4 kg silica gel) using 2:1heptane/ethyl acetate (15 L) as eluent. The fractions containing theproduct were combined and concentrated under reduced pressure at 35° C.to afford a mixture of the title compounds as a light brown oil [1785 g,90%). The ¹H NMR spectrum was consistent with the assigned structure andindicated the presence of a 64:36 ratio of regioisomers.

c)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and a condenser with a nitrogen inlet wascharged with a mixture of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile [600 g,2.69 mol, as prepared in the previous step) and carbon tetrachloride(1.8 L). Agitation was initiated and the mixture was heated to 60° C. Atthis point N-bromosuccinimide (502 g, 2.82 mol) was added in severalportions over 30 min, which resulted in an exotherm to 74° C. Thereaction was allowed to cool to 60° C. and further stirred at 60° C. for1 h. The reaction was allowed to cool slowly to ambient temperature andthe resulting slurry was filtered and the filtrate washed with satdNaHCO₃ solution (4.0 L). The organics were passed through a plug ofsilica gel (8×15 cm, silica gel; 600 g) using 2:1 heptane/ethyl acetate(6.0 L) as eluent. The fractions containing the product (based on TLCanalysis) were combined and concentrated under reduced pressure to givea crystalline light yellow solid, which was then filtered and washedwith heptane (500 mL) to give the title compound as a crystalline whitesolid [593 g, 73%). The ¹H and ¹³C NMR spectra were consistent with theassigned structure and showed no evidence of the minor regioisomer.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

A 12-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile[390 g, 1.29 mol, as prepared in the previous step) and anhydroustetrahydrofuran (4.0 L). Agitation was initiated and the reactionmixture was cooled to −50° C. using a dry ice/acetone bath.Isopropylmagnesium chloride (2.0 M in THF, 760 mL, 1.52 mol) was addedthrough the addition funnel over 30 min to maintain the internaltemperature below −40° C. The reaction was stirred for a further 30 minat −43° C., after which time it was cooled to −78° C. Ethylchloroformate (210 mL, 2.20 mol) was added through the addition funnelover 10 min to maintain the internal temperature below −60° C. Thereaction was stirred for a further 40 min at −70° C., at which point thedry ice/acetone bath was removed and the reaction was allowed to warm toambient temperature over 1.5 h. The reaction mixture was cooled in anice bath to 0° C. and quenched by the slow addition of satd ammoniumchloride solution (1.8 L) at such a rate that the internal temperaturewas maintained below 10° C. The reaction mixture was transferred into a12-L separatory funnel, diluted with ethyl acetate (4.0 L), and thelayers were separated. The organic layer was washed with brine (2×2.0 L)and concentrated under reduced pressure at 35° C. to give a brown oil.The crude oil was dissolved in dichloromethane (300 mL) and purified bychromatography (15×22 cm, 1.5 kg of silica gel, 10:1 to 4:1heptane/ethyl acetate) to give a yellow oil, which was dissolved inEtOAc (100 mL), diluted with heptane (2.0 L), and stored in arefrigerator for 5 h. The resulting slurry was filtered to give thetitle compound as a crystalline white solid (141 g, 37%). The ¹H and ¹³CNMR spectra were consistent with the assigned structure.

e) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

A 5-L, three-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with 5 [400 g, 1.35 mol) and ethanol (4.0 L).Agitation was initiated and a water bath was applied after all of thesolid had dissolved. A solution of 6 N KOH (214.0 mL, 1.29 mol) wasadded through the addition funnel over 15 min to maintain the internaltemperature below 25° C. and the reaction was stirred for 5 min at roomtemperature. The solution was then concentrated to dryness under reducedpressure at 20° C. to give a white solid. The resulting solid wassuspended in methyl t-butyl ether (MTBE, 4.0 L) and stirred for 30 min,after which time the slurry was filtered and the filter cake washed withMTBE (1.0 L) to give the title compound as a white solid, which wasfurther dried under vacuum at ambient temperature for 4 d [366 g, 89%).The ¹H NMR, ¹³C NMR, and mass spectra were consistent with the assignedstructure. Anal. Calcd for C₁₁H₁₆KN₃O₃Si: C, 43.25; H, 5.28; N, 13.76.Found: C, 42.77; H, 5.15; N, 13.37. Karl Fisher: 1.3% H₂O.

EXAMPLE 60 5-Cyano-1H-imidazole-2-carboxylic acid[4-(3,6-dihydro-2H-pyran-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A flask charged with imidazole-4-carbonitrile (0.5 g, 5.2 mmol)(Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl)(0.95 mL, 5.3 mmol), K₂CO₃ (1.40 g, 10.4 mmol), and acetone (5 mL) wasstirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) andwashed with water (20 mL) and brine (20 mL) and the organic layer driedover MgSO₄. The crude product was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the titlecompound as a colorless oil: Mass spectrum (CI(CH₄), m/z) Calcd. forC₁₀H₁₇N₃OSi, 224.1 (M+H), found 224.1.

b)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4carbonitrile

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g,3.1 mmol) (as prepared in the previous step) in CCl₄ (10 mL) was addedNBS (0.61 g, 3.4 mmol) and AIBN (cat), and the mixture heated at 60° C.for 4 h. The reaction was diluted with EtOAc (30 mL) and washed withNaHCO₃ (2×30 mL) and brine (30 mL) and the organic layer was dried overNa₂SO₄ and then concentrated. The title compound was eluted from a 20-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.73 g (77%) of ayellow solid: Mass spectrum (CI(CH₄), m/z) Calcd. for C₁₀H₁₆BrN₃OSi,302.0/304.0 (M+H), found 302.1/304.1.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile(0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at−40° C. was added drop wise a solution of 2M i-PrMgCl in THF (1 mL). Thereaction was allowed to stir for 10 min at −40° C. and then cooled to−78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. Thereaction allowed to attain RT and stirred for 1 h. The reaction wasquenched with satd aq NH4Cl, diluted with EtOAc (20 mL) and washed withbrine (2×20 mL), and the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.4 g (74%) of a colorless oil:Mass spectrum (ESI, m/z): Calcd. for C₁₃H₂₁N₃O₃Si, 296.1 (M+H), found296.1.

d)4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (0.4 g, 1.3 mmol) (as prepared in the previous step) inethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and the reactionwas stirred for 10 min and then concentrated to give 0.40 g (100%) ofthe title compound as a yellow solid: 1H-NMR (400 MHz, CD₃OD) δ 7.98 (s,1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). Massspectrum (ESI-neg, m/z) Calcd. for C₁₁H₁₆N₃KO₃Si, 266.1 (M−K), found266.0.

e) 4-Bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine

A flask is charged with 4-bromo-2-iodo-phenylamine (1.10 g, 3.70 mmol),4,4-dimethylcyclohexen-1-ylboronic acid (0.630 g, 4.07 mmol), Pd(PPh₃)₄(0.240 g, 5 mol %), 2 M Na₂CO₃ (16 mL), EtOH (16 mL) and toluene (32 mL)and heated at 80° C. for 6 h. The reaction was diluted with EtOAc (100mL) and washed with saturated aqueous NaHCO₃ (2×100 mL) and brine (100mL), and the organic layer dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash silica gel chromatography eluting with 10%EtOAc/hexane to give 0.68 g (66%) of the title compound as a lightyellow oil: Mass spectrum (ESI, m/z) calcd. for C₁₄H₁₈BrN, 280.1 (M+H),found 280.1.

f) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide

To a suspension of 4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine(0.640 g, 2.29 mmol, as prepared in the previous step) and4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (0.700 g, 2.30 mmol, as prepared in this Example, step(d)) in DCM (12 mL) was added DIPEA (0.800 mL, 4.60 mmol) and PyBrOP(1.29 g, 2.76 mmol) and the mixture allowed to stir at RT for 10 h. Themixture was diluted with DCM (50 mL) and washed with NaHCO₃ (2×50 mL)and the organic layer dried over Na₂SO₄ and concentrated. The titlecompound was eluted from a 20-g SPE with 1:1 DCM/hexane to give 1.04 g(86%) of a white solid: Mass spectrum (ESI, m/z) calcd. forC₂₅H₃₃BrN₄O₂Si, 529.1 (M+H), found 529.1.

g) 4-Cyano-1H-imidazole-2-carboxylic acid[4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (0.950 g,1.80 mmol, as prepared in the previous step) in 10 mL of DCM was added0.4 mL of EtOH and 10 mL of TFA and the mixture stirred for 1 h at RT.The mixture was concentrated and triturated with Et₂O to give 0.68 g(95%) of the title compound as a white solid: 1H-NMR (400 MHz, CDCl₃) δ11.23 (br s, 1H), 9.52 (br s, 1H), 8.27 (d, J=8.7 Hz, 1H), 7.72 (s, 1H),7.41 (dd, J=2.3, 8.7 Hz, 1H), 7.33 (d, J=2.3Hz, 1H), 5.82 (m, 1H), 2.28(m, 2H), 2.10 (m, 2H), 1.58 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI,m/z) calcd. for C₁₉H₁₉BrN₄O 399.1 (M+H), found 399.0.

h) 5-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide

To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid[4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (0.550 g, 1.38mmol, as prepared in the previous step) in 20 mL THF at −40° C. wasadded i-PrMgCl (1.40 mL, 2 M in THF) and the solution was then warmed to0° C. and stirred for 10 min. The solution was then cooled to −78° C.and t-BuLi (2.15 mL, 1.7 M in pentane) was added dropwise over 5 min andthen tetrahydropyran-4-one (0.650 mL, 7.05 mmol) was added immediatelythereafter. After 5 min at −78° C. the reaction was quenched with satdNH₄Cl (20 mL) and extracted with EtOAc (3×20 mL) and dried over Na₂SO₄.The title compound was purified by flash chromatography (silica gel)eluting with 50% EtOAc/DCM to give 0.46 g (79%) of a white solid: ¹H-NMR(400 MHz, DMSO-d6) δ 14.28 (s, 1H), 9.77 (s, 1H), 8.21 (s, 1H), 7.98 (d,J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 2.2 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H),5.67 (m, 1H), 5.03 (s, 1H), 3.83-3.66 (m, 4H), 2.31-2.22 (m, 2H),2.04-1.92 (m, 4H), 1.58-1.46 (m, 4H), 1.01 (s, 6H). Mass spectrum (ESI,m/z) calcd. for C₂₄H₂₈N₄O₃ 421.2 (M+H), found 421.1.

i) 5-Cyano-1H-imidazole-2-carboxylic acid[4-(3,6-dihydro-2H-pyran-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide

To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl )-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (16.0 mg, 38.1 μmol, as prepared in the previous step)in 0.3 mL of toluene was added p-toluenesulfonic acid (14.0 mg, 74.0mmol) and the mixture heated to 60° C. for 2 h. The solvent wasevaporated and the title compound purified by RP-HPLC, eluting with alinear gradient of 40% CH₃CN in 0.1% TFA/H₂O to 100% CH₃CN over 20 minto give 8.0 mg (50%) of a white solid: ¹H-NMR (400 MHz, CD₃OD) δ 8.23(d, J=8.6 Hz, 1H), 8.02 (s, 1H), 7.38 (dd, J=8.6, 2.2 Hz, 1H), 7.26 (d,J=2.2 Hz, 1H), 6.20 (m, 1H), 5.78 (m, 1H), 4.32 (m, 2H), 3.94 (t, J=5.5,5.5 Hz, 2H), 2.53 (m, 2H), 2.34 (m, 2H), 2.10 (m, 2H), 1.62 (t, J=6.3,6.3 Hz, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z) calcd. forC₂₄H₂₆N₄O₂ 403.2 (M+H), found 403.2.

EXAMPLE 61 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohept-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

a) 4-(4-Amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

To a mixture of4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (Synthesis, 993, (1991), 7.4 g, 22 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4.0 g, 18mmol) and Pd(PPh₃)₄ (2.3 g, 2.0 mmol) in 160 mL of toluene and 80 mL ofabsolute ethanol under Ar was added 2.0 M aq Na₂CO₃ solution (80 mL, 160mmol). The resulting mixture was stirred at 80° C. for 3 h and thencooled to RT. After adding 600 mL of EtOAc, the mixture was washed with1 M NaOH (250 mL), H₂O (2×250 mL), brine (300 mL) and dried (Na₂SO₄).Removal of the solvent under reduced pressure followed by flashchromatography of the residue on silica gel (20% EtOAc/hexane) gave 3.20g (63%) of the title compound as a hard yellow foam: Mass spectrum (ESI,m/z): Calcd. for C₁₆H₂₂N₂O₂, 275.2 (M+H), found 275.1.

b) 4-(4-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.35 g, 1.2 mmol, as prepared in the previousstep) in 30 mL methanol was hydrogenated over 10% Pd/C at 20 psi for 1h. The solution was filtered and concentrated to give 0.35 g (100%) ofthe title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd.for C₁₆H₂₄N₂O₂, 277.2 (M+H), found 277.1.

c) 4-(4-Amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butylester

A solution of 2.00 g (7.24 mmol)4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (asprepared in the previous step) in 40 mL of CH₃CN was treated with solid1.25 g (7.02 mmol) NBS and stirred at RT for 15 min. The solvents wereevaporated in vacuo, the residue was taken up in EtOAc (70 mL) andwashed with saturated aqueous NaHCO₃ (2×50 mL). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo. Silica gelchromatography of the residue with 10-25% EtOAc-hexanes afforded 3.12 g(97%) of the title compound as a tan solid: Mass spectrum (ESI, m/z):Calcd. for C₁₂H₁₆N₂O₂Br, 299.0 (M−C₄H₉+2H), found 299.1/301.1.

d) 4-(4-Amino-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

A solution of 230 mg (0.647 mmol)4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester(as prepared in the previous step) in 6 mL toluene and 3 mL EtOH wastreated with 118 mg (0.842 mmol) cyclohept-1-enylboronic acid and 2.60mL (5.18 mmol) 2.0 M Na₂CO₃. The mixture was degassed via sonication,placed under Ar, treated with 52.3 mg (0.0453 mmol) Pd(PPh₃)₄, andheated to 85° C. for 23 h. The mixture was diluted with EtOAc (15 mL)and washed with water (1×15 mL) and brine (1×15 mL). The combinedaqueous layers were extracted with EtOAc (15 mL), and the combinedorganic layers were dried (MgSO₄) and concentrated in vacuo. Silica gelchromatography of the residue on a Varian MegaBond Elut 50-gm columnwith 10-18% EtOAc-hexane afforded 108 mg (45%) of the title compound asa tan solid: Mass spectrum (ESI, m/z): Calcd. for C₁₉H₂₇N₂O₂, 315.2(M−C₄H₉+2H), found 315.2.

e)4(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

A solution of 108 mg (0.292 mmol)4-(4-amino-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (as prepared in the previous step) in 10 mL CH₂Cl₂ wastreated with 97.9 mg (0.321 mmol)4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 1, step (d)), 204 mg (0.437 mmol)PyBrOP, and 152 μL (0.874 mmol) DIEA and stirred at RT for 17 h. Themixture was diluted with CH₂Cl₂ (20 mL) and washed with saturated NaHCO₃(1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO₄) andconcentrated in vacuo. Silica gel chromatography of the residue on aVarian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 160mg (88%) of the title compound as an off-white solid: Mass spectrum(ESI, m/z): Calcd. for C₃₀H₄₂N₅O₄Si, 563.3 (M−C₄H₉+2H), found 563.9.

f) 4-Cyano-1H-imidazole-2-caboxylic acid(2-cyclohept-1-enyl-4-piperidin-4-yl-phenyl)-amide

A solution of 160 mg (0.258 mmol)4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohept-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step) in 10 mL CH₂Cl₂was treated with 200 μL MeOH and 3 mL TFA at RT for 3.5 h. Solvents wereevaporated in vacuo. The residue was taken up in CH₂Cl₂ (30 mL) andwashed with saturated aqueous NaHCO₃ (1×20 mL). The organic layer wasdried (MgSO₄) and concentrated in vacuo to afford 100 mg (100%) of thetitle compound as a white solid: Mass spectrum (ESI, m/z): Calcd. forC₂₃H₂₇N₅O, 390.2 (M+H), found 390.3.

g) 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohept-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

A suspension of 39.7 mg (0.385 mmol) dimethylamino-acetic acid in 5 mLCH₂Cl₂ was treated with 94.8 mg (0.372 mmol) BOP—Cl and 143 μL (1.03mmol) triethylamine at RT for 1 h. This mixture was added to asuspension of 100 mg (0.257 mmol) 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohept-1-enyl-4-piperidin-4-yl-phenyl)-amide (as prepared in theprevious step) in 5 mL CH₂Cl₂. The mixture stirred at RT for 22 h, wasdiluted with CH₂Cl₂ (15 mL), and washed with saturated aqueous NaHCO₃(10 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo.Purification of the residue by RP-HPLC (C18) with 20-60% CH₃CN in 0.1%TFA/H₂0 over 30 min to afford 32.1 mg (21%) of the title compound as awhite solid: ¹H-NMR (CD₃OD; 400 MHz): δ 8.09 (d, 1H, J=8.4 Hz), 8.03 (brs, 1H), 7.18 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.07 (d, 1H, J=2.4 Hz), 5.98(t, 1H, J=6.4 Hz), 4.72-4.64 (m, 1H), 4.31 (q, 2H, J=16.4 Hz), 3.83-3.75(m, 1H), 3.31-3.22 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.81 (m, 2H),2.54-2.47 (m, 2H), 2.43-2.35 (m, 2H), 1.99-1.87 (m, 4H), 1.83-1.68 (m,6H), 1.69-1.59 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₃₄N₆O₂,475.3 (M+H), found 475.3.

EXAMPLE 62 4-Cyano-1H-imidazole-2-carboxylic acid[4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amidetrifluoroacetic acid salt

a)4-[4-Amino-3-(4,4dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-4-carboxylicacid tert-butyl ester

A solution of 250 mg (0.704 mmol)4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester(as prepared in Example 61, step (c)) in 6 mL toluene and 3 mL EtOH wastreated with 119 mg (0.774 mmol) 4,4-dimethyl-cyclohex-1-enylboronicacid and 2.81 mL (5.63 mmol) 2.0 M Na₂CO₃. The mixture was degassed viasonication, placed under Ar, treated with 56.9 mg (0.0493 mmol)Pd(PPh₃)₄, and heated to 85° C. for 27 h and allowed to stand at RT for36 h. The mixture was diluted with EtOAc (15 mL) and washed with water(1×15 mL). The combined aqueous layers were extracted with EtOAc (15mL), and the combined organic layers were dried (MgSO₄) and concentratedin vacuo. Silica gel chromatography of the residue on a Varian MegaBondElut 50-gm column with 10-15% EtOAc-hexane afforded 89.0 mg (33%) of thetitle compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. forC₂₀H₂₉N₂O₂, 329.2 (M—C₄H₉+2H), found 329.2.

b)4-[4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of 89.0 mg (0.231 mmol)4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step) in 10 mL CH₂Cl₂was treated with 77.8 mg (0.255 mmol)4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 1, step (d)), 162 mg (0.347 mmol)PyBrOP, and 121 μL (0.694 mmol) DIEA and stirred at RT for 2 h. Themixture was diluted with CH₂Cl₂ (20 mL) and washed with saturated NaHCO₃(1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO₄) andconcentrated in vacuo. Silica gel chromatography of the residue on aVarian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 124mg (84%) of the title compound as an off-white solid: Mass spectrum(ESI, m/z): Calcd. for C₃₁H₄₄N₅O₄Si, 578.3 (M−C₄H₉+2H), found 578.0.

c) 4-Cyano-1H-imidazole-2-carboxylicacid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide

A solution of 124 mg (0.196 mmol)4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step) in 10 mL CH₂Cl₂was treated with 200 μL MeOH and 3 mL TFA at RT for 3.5 h. Solvents wereevaporated in vacuo. The residue was taken up in CH₂Cl₂ (30 mL) andwashed with saturated aqueous NaHCO₃ (1×20 mL). The organic layer wasdried (MgSO₄) and concentrated in vacuo to afford 70.0 mg (89%) of thetitle compound as a white solid: Mass spectrum (ESI, m/z): Calcd. forC₂₄H₂₉N₅O, 404.2 (M+H), found 404.3.

d) 4-Cyano-1H-imidazole-2-carboxylic acid[4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amidetrifluoroacetic acid salt

A suspension of 26.8 mg (0.260 mmol) dimethylamino-acetic acid in 4 mLCH₂Cl₂ was treated with 64.0 mg (0.372 mmol) BOP—Cl and 96.7 μL (0.694mmol) triethylamine at RT for 1 h. This mixture was added to asuspension of 70.0 mg (0.173 mmol) 4-cyano-1H-imidazole-2-carboxylicacid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide(as prepared in the previous step) in 5 mL CH₂Cl₂. The mixture stirredat RT for 17 h, was diluted with CH₂Cl₂ (15 mL), and washed withsaturated aqueous NaHCO₃ (10 mL). The organic layer was dried (MgSO₄)and concentrated in vacuo. Purification of the residue by RP-HPLC (C18)with 20-60% CH₃CN in 0.1% TFA/H₂O over 30 min to afford 57.3 mg (55%) ofthe title compound as a white solid: ¹H-NMR (CD₃OD; 400 MHz): δ 8.15 (d,1H, J=8.4 Hz), 8.02 (s, 1H), 7.20 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.10 (d,1H, J=2.0 Hz), 5.77-5.72 (m, 1H), 4.72-4.64 (m, 1H), 4.30 (q, 2H, J=16.0Hz), 3.83-3.75 (m, 1H), 3.30-3.21 (m, 1H), 2.98 (d, 6H, J=9.2 Hz),2.93-2.81 (m, 2H), 2.36-2.28 (m, 2H), 2.11-2.06 (m, 2H), 1.99-1.90 (m,2H), 1.82-1.62 (m, 2H), 1.61 (t, 2H, J=6.4 Hz), 1.10 (s, 6H). Massspectrum (ESI, m/z): Calcd. for C₂₇H₃₄N₆O₂, 475.3 (M+H), found 475.3.Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₆N₆O₂, 489.3 (M+H), found489.4.

EXAMPLE 63 4-Cyano-1H-pyrrole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

a) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

A solution of 500 mg (1.41 mmol)4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester(as prepared in Example 61, step (c)) in 11.2 mL toluene and 5.6 mL EtOHwas treated with 5.63 mL (11.3 mmol) 2.0 M aqueous Na₂CO₃ and 381 mg(1.83 mmol) 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[I,3,2]dioxaborolane.The mixture was degassed via sonication, placed under Ar, treated with163 mg (0.141 mmol) Pd(PPh₃)₄, and heated to 80° C. for 22 h. Themixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL).The combined aqueous layers were extracted with EtOAc (1×30 mL) and thecombined organic layers were dried (MgSO₄) and concentrated in vacuo.Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gmcolumn with 10-25% EtOAc-hexanes afforded 445 mg (89%) as a tan solid:Mass spectrum (ESI, m/z): Calcd. for C₁₈H₂₅N₂O₂, 301.2 (M−C₄H₉+2H),found 301.2.

b)4-{4-[(4-Cyano-1H-pyrrole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A suspension of 101 mg (0.741 mmol) 4-cyano-1H-pyrrole-2-carboxylic acid(Canadian J. Chem. 59: 2673 (1981)) in 20 mL CH₃CN was treated with 116μL (0.741 mmol) (1-chloro-2-methyl-propenyl)-dimethylamine at RT for 20min. The mixture was added to a solution of 220 mg (0.617 mmol) of4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (as prepared in the previous step) in 10 mL CH₃CN,stirred at RT for 20 h and the solvents evaporated in vacuo. Silica gelchromatography of the residue on a Varian MegaBond Elut 25-gm columnwith 10-25% EtOAc-hexane afforded 36.0 mg (12%) of the title compound asan off-white solid: Mass spectrum (ESI, m/z): Calcd. for C₂₄H₂₇N₄O₃,419.2 (M−C₄H₉+2H), found 419.1.

c) 4-Cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

A solution of 36.0 mg (0.0759 mmol)4-{4-[(4-cyano-1H-pyrrole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step) in 5 mL CH₂Cl₂was treated with 4 drops MeOH and 1 mL TFA and stirred at RT for 2 h.MeOH (5 mL) was added, and solvents were evaporated in vacuo.Purification of the residue by RP-HPLC (C18) with 10-80% CH₃CN in 0.1%TFA/H₂O over 30 min afforded 22.0 mg (59%) of the title compound as awhite solid: Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₆N₄O, 375.2(M+H), found 375.2.

d) 4-Cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl)-amidetrifluoroacetic acid salt

A suspension of 9.10 mg (0.0881 mmol) dimethylamino-acetic acid in 5 mLCH₂Cl₂ was treated with 21.7 mg (0.0852 mmol) BOP—Cl and 32.8 μL (0.235mmol) triethylamine at RT for 50 min. This mixture was added to asuspension of 22.0 mg (0.0588 mmol) 4-cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in the previous step) in 5 mL CH₂Cl₂. The mixturestirred at RT for 23 h, was diluted with CH₂Cl₂ (15 mL), and washed withsaturated aqueous NaHCO₃ (1×10 mL). The organic layer was dried (MgSO₄)and concentrated in vacuo. Purification of the residue by RP-HPLC (C18)with 20-80% CH₃CN in 0.1% TFA/H₂O over 30 min to afford 33.6 mg (83%) ofthe title compound as a white solid: ¹H-NMR (CD₃OD; 400 MHz): δ 7.54 (d,1H, J=1.6 Hz), 7.41 (d, 1H, J=8.0 Hz), 7.14 (dd, 1H, J=8.4 Hz, J=2.0Hz), 7.12-7.08 (m, 1H), 7.07 (d, 1H, J=2.0 Hz), 5.70-5.65 (m, 1H),4.67-4.59 (m, 1H), 4.26 (q, 2H, J=16.4 Hz), 3.78-3.70 (m, 1H), 3.26-3.17(m, 1H), 2.97-2.89 (m, 6H), 2.88-2.75 (m, 2H), 2.25-2.18 (m, 2H),2.15-2.07 (m, 2H), 1.94-1.85 (m, 2H), 1.76-1.54 (m, 6H). Mass spectrum(ESI, m/z): Calcd. for C₂₇H₃₃N₅O₂, 460.3 (M+H), found 460.3.

EXAMPLE 64 4-Cyano-1-imidazole-2-carboxilic acid(2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

a) Methanesulfonic acid 2-methanesulfonyl-ethyl ester

To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mLof CH₂Cl₂ at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03mmol) in 10 mL of CH₂Cl₂ followed by DIEA (1.05 mL, 6.05 mmol) under Ar.The mixture was warmed to RT and stirred for 20 h under Ar. The mixturewas treated with 100 mL of EtOAc and washed with H₂O (3×20 mL), brine(20 mL) and dried (Na₂SO₄). Removal of the solvent in vacuo gave 534 mg(66%) of the title compound as a brown oil: ¹H-NMR (CDCl₃; 400 MHz): δ4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s,3H).

b) 4-Cyano-1-imidazole-2-carboxilic acid{2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl)-amidetrifluoroacetic acid salt

A solution of 522 mg (1.01 mmol) of 4-cyano-1H-imidazole-2-carboxylicacid[2-(4,4-dimethyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide (asprepared in Example 62, step (c)) in 30 mL CH₂Cl₂ was treated with 245mg (1.21 mmol) methanesulfonic acid 2-methanesulfonyl-ethyl ester (asprepared in the previous step) and 527 μL (3.03 mmol) DIEA and stirredat RT for 25 h. The mixture was diluted with CH₂Cl₂ (50 mL) and washedwith saturated aqueous NaHCO₃ (1×50 mL). The organic layer was dried(MgSO₄) and concentrated in vacuo. The residue was purified by RP-HPLC(C18) with 30-50% CH₃CN in 0.1% TFA/H₂O over 30 min to afford 15.3 mg(3%) of the title compound as a white solid: 1H-NMR (CD₃OD; 400 MHz): δ8.20 (d, 1H, J=8.8 Hz), 8.02 (s, 1H), 7.26-7.19 (m, 1H), 7.16-7.10 (m,1H), 5.78-5.73 (m, 1H), 3.83-3.63 (m, 6H), 3.29-3.17 (m, 2H), 3.14 (s,3H), 2.99-2.88 (m, 1H), 2.37-2.28 (m, 2H), 2.23-2.13 (m, 2H), 2.12-2.07(m, 2H), 2.07-1.93 (m. 2H), 1.61 (t, 2H, J=6.0 Hz), 1.10 (s, 6H). Massspectrum (ESI, m/z): Calcd. for C₂₇H₃₅N₅O₃S, 510.3 (M+H), found 510.2.

IV. Results

An autophosphorylation, fluorescence polarization competitionimmunoassay was used to determine the potency for c-fms inhibitionexhibited by selected compounds of Formula I. The assay was performed inblack 96-well microplates (LJL BioSystems). The assay buffer used was100 mM 4-(2-hydroxyethyl)piperazine 1-ethanesulfonic acid (HEPES), pH7.5, 1 mM 1,4-dithio-DL-threitol (DTT), 0.01% (v/v) Tween-20. Compoundswere diluted in assay buffer containing 4% dimethylsulfoxide (DMSO) justprior to the assay. To each well, 5 μL of compound were added followedby the addition of 3 μL of a mix containing 33 nM c-fms (Johnson &Johnson PRD) and 16.7 mM MgCl₂ (Sigma) in assay buffer. The kinasereaction was initiated by adding 2 μL of 5 mM ATP (Sigma) in assaybuffer. The final concentrations in the assay were 10 nM c-fms, 1 mMATP, 5 mM MgCl₂, 2% DMSO. Control reactions were ran in each plate: inpositive and negative control wells, assay buffer (made 4% in DMSO) wassubstituted for the compound; in addition, positive control wellsreceived 1.2 μL of 50 mM ethylenediaminetetraaceticacid (EDTA).

The plates were incubated at room temperature for 45 min. At the end ofthe incubation, the reaction was quenched with 1.2 μL of 50 mM EDTA(EDTA was not added to the positive control wells at this point; seeabove). Following a 5-min incubation, each well received 10 μL of a1:1:3 mixture of anti-phosphotyrosine antibody, 10X, PTK green tracer,10X (vortexed), FP dilution buffer, respectively (all from PanVera, cat.# P2837). The plate was covered, incubated for 30 min at roomtemperature and the fluorescence polarization was read on the Analyst.The instrument settings were: 485 nm excitation filter; 530 nm emissionfilter; Z height: middle of well; G factor: 0.93. Under theseconditions, the fluorescence polarization values for positive andnegative controls were approximately 300 and 150, respectively, and wereused to define the 100% and 0% inhibition of the c-fms reaction. Thereported IC₅₀ values are averages of three independent measurements.

Table 1 lists representative compounds of the invention. TABLE 1 c-finsIC50 Example # Structure (μM)  4

0.47  5

0.95  6

0.0016  7

0.0043  8

0.001  9

0.63 10

0.9 11

0.012 12

0.06 13

0.012 14

0.018 15

0.028 16

0.0026 17

0.00055 18

0.0082 20

0.002 21

0.0024 22

0.0014 23

0.0066 24

0.0046 25

0.022 26

0.0011 27

0.0016 28

0.0014 29

0.0025 30

0.001 31

0.0014 32

0.0018 33

0.0011 34

0.0018 35

0.0029 36

0.060 37

0.060 38

0.0024  38b

0.0014 39

0.00095 40

0.0019 41

0.0013 42

0.0014 43

0.0031 44

0.00095 45

0.001 46

N/A 47

0.0013 48

0.00064 49

0.060 50

0.060  51a

0.00020  51b

0.0004 52

0.0012 53

0.0053 54

0.0008 55

0.0007 56

0.001 57

0.0013 58

0.0070

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

All publications disclosed in the above specification are herebyincorporated by reference in full.

1. The novel compounds of Formula I:

or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: A is phenyl or pyridyl, either of which may be substituted with one of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl), or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl, any of which may be connected through any carbon atom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain one —Cl, —CN, —NO₂, —OMe, or —CF₃ substitution, connected to any other carbon; R² is cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chloro, fluoro, and C₍₁₋₃₎alkyl, with the proviso that tetrahydropyridyl is connected to the ring A through a carbon-carbon bond; X is

Z is CH or N; D¹ and D² are each hydrogen or taken together form a double bond to an oxygen; D³ and D⁴ are each hydrogen or taken together form a double bond to an oxygen; D⁵ is hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented syn or anti; R_(a) and R_(b) are independently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; E is N, S, O, SO or SO₂, with the proviso that E may not be N if the following three conditions are simultaneously met: Q_(a) is absent, Q_(b) is absent, and R³ is an amino group or cyclic amino radical wherein the point of attachment to E is N; Q_(a) is absent, —CH₂—, —CH₂CH₂—, or C(O); Q_(b) is absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that Q_(b) may not be C(O) if Q_(a) is C(O), and further provided that Q_(b) may not be —NH— if E is N and Q_(a) is absent, further provided that Q_(b) may not be —NH— if R³is an amino group or cyclic amino radical wherein the point of attachment to Q_(b) is N; R³ is hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered ring which contains at least one heteroatom N and may optionally contain an additional heteromoiety selected from S, SO₂, N, and O, and the 5 or 6 membered ring may be saturated, partially unsaturated or aromatic, wherein aromatic nitrogen in the 5 or 6 membered ring may be present as N-oxide, and the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino, or alkoxy; R³ may also be absent, with the proviso that R³ is not absent when E is nitrogen; R⁴is hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.
 2. A compound of claim 1 wherein W is substituted with one —CN.
 3. A compound of claim 1 wherein A is pyridyl, which may be substituted with one of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl), or 4-aminophenyl; W is imidazolyl, (including 1H-imidazol-2-yl), which may contain one —CN; and R² is cycloalkyl.
 4. A compound of claim 1 wherein: W is imidazolyl, 1,2,4 triazolyl, or furanyl any of which may be connected through any carbon atom, wherein the imidazolyl, 1,2,4 triazolyl, or furanyl may contain one —Cl or —CN, connected to any other carbon; R² is cycloalkyl, thiophenyl, C₍₁₋₃₎alkyl substituted phenyl, dihydropyranyl, and 1,1-dioxo-tetrahydrothiopyranyl; X is

E is N or SO₂, with the proviso that E may not be N if the following three conditions are simultaneously met: Q_(a) is absent, Q_(b) is absent, and R³is an amino group or cyclic amino radical wherein the point of attachment to E is N; and R³ is hydrogen, phenyl, hydroxyalkylamino, hydroxyalkyl(alkyl)amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, or a 5 or six membered ring selected from the group consisting of: piperidinyl, morpholinyl, imidazolyl, and pyridyl, wherein the 5 or 6 membered ring may be optionally substituted with methyl, halogen, alkylamino, or alkoxy, R³ may also be absent, with the proviso that R³ is not absent when E is nitrogen.
 5. A compound of claim 1 wherein: A is phenyl which may be substituted with one of chloro, fluoro, or methyl; X is

and is attached to the phenyl A ring para to the nitrogen substituent, as depicted in formula II;

D³ and D⁴are hydrogen; E is N or SO₂, with the proviso that E may not be N if the following three conditions are simultaneously met: Q_(a) is absent, Q_(b) is absent, and R³is an amino group or cyclic amino radical wherein the point of attachment to E is N; and R³ is hydrogen, piperidinyl, alkylamino, dialkylamino, hydroxyalkylamino, (hydroxyalkyl)₂amino, imidazolyl, 1-methyl imidazolyl, pyridyl, pyridyl N-oxide, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, morpholinyl; R³ may also be absent, with the proviso that R³ is not absent when E is nitrogen.
 6. A compound of claim 5 wherein: A is phenyl; W is furan-2-yl, 1H-pyrrol-2-yl, or 1H-imidazol-2-yl, any of which may be substituted at the 4 or 5 carbons with —CN; R² is cycloalkyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which may be independently substituted with one or two of each of the substituents selected from the group consisting of chloro, fluoro, and C₍₁₋₃₎alkyl, with the proviso that tetrahydropyridyl must be connected to the ring A through a carbon-carbon bond.
 7. A compound of claim 6 wherein: W is 3H-2-imidazolyl-4-carbonitrile or 5-cyano-1H-pyrrol-2-yl; R² is cyclohexenyl, or cyclopentenyl, either of which may be substituted with chloro, fluoro or one or two C₁₋₃₎alkyl groups; E is N, with the proviso that E may not be N if the following three conditions are simultaneously met: Q_(a) is absent, Q_(b) is absent, and R³is an amino group or cyclic amino radical wherein the point of attachment to E is N; Z is CH.
 8. A compound of claim 7 wherein: W is 3H-2-imidazolyl-4-carbonitrile; Q_(a) is CO; R³ is hydrogen, piperidinyl, hydroxyalkylamino, (hydroxyalkyl)₂amino, alkylamino, dialkylamino, imidazolyl, 1-methyl imidadolyl, pyridinyl, pyridinyl N-oxide, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂CH₃, —NH₂, morpholinyl.
 9. A compound selected from the group consisting of: 5-cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-(2-methyl-thiophen-3-yl )-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide, 5-cyano-furan-2-carboxylic acid [2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide, (4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-acetic acid, 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-carbamoylmethyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-cyano-ethyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide, 4-cyano-1H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-phenyl]-amide, 4-cyano-1H-pyrrole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-4-carbonyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-phenyl}-amide, 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylic acid amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide, 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-carboxylic acid (2-hydroxy-ethyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-3H-imidazol-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-{2-[(2-hydroxy-ethyl)-methyl-amino]-acetyl}-piperidin-4-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-Cyano-1H-imidazole-2-carboxylic acid {4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide trifluoroacetic acid salt, 4H-[1,2,4]-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroacetic acid salt, 5-Chloro-4H-[1,2,4]-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bis trifluoroacetic acid salt, 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bis trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide, 5-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide trifluoroacetic acid salt, 4-Cyano-1H-imidazole-2-carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid [6-cyclohex-1-enyl-1-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide, 4-Cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-Cyano-1H-imidazole-2-carboxylic acid [1′-(2-dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt, 4-Cyano-1H-imidazole-2-carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid [4-(3,6-dihydro-2H-pyran-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide; 4-Cyano-1H-imidazole-2-carboxylic acid {2-cyclohept-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide trifluoroacetic acid salt; 4-Cyano-1H-imidazole-2-carboxylic acid [4-[1-(2-dimethylamino-acetyl)-piperidin-4 -yl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide trifluoroacetic acid salt; 4-Cyano-1H-pyrrole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide trifluoroacetic acid salt; 4-Cyano-1-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide trifluoroacetic acid salt; and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 10. A compound of claim 5, selected from the group consisting of: 5-cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl )-phenyl]-amide, and 5-cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-(2-methyl-thiophen-3-yl)-phenyl]-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 11. A compound of claim 6, selected from the group consisting of: 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl )-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl )-phenyl]-amide, 5-cyano-furan-2-carboxylic acid [2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide and 5-cyano-furan-2-carboxylic acid [2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 12. A compound of claim 7, selected from the group consisting of: (4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-acetic acid, 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-carbamoylmethyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-cyano-ethyl)-piperidin4-yl]-2-cyclohex-1-enyl-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide, 4-cyano-1H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-phenyl]-amide, and 4-cyano-1H-pyrrole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 13. A compound of claim 8 selected from the group consisting of: 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-4-carbonyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-phenyl}-amide, 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylic acid amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide, 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine 1-carboxylic acid (2-hydroxy-ethyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-3H-imidazol-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-phenyl 1-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, and 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 14. A compound which is: 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-{2-[(2-hydroxy-ethyl)-methyl-amino]-acetyl}-piperidin-4-yl)-phenyl ]-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 15. A compound which is: 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 16. A compound which is: 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 17. A compound selected from the group consisting of: 4-Cyano-1H-imidazole-2-carboxylic acid {4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide trifluoroacetic acid salt, 4H-[1,2,4]-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroacetic acid salt, 5Chloro-4H-[1,2,4]-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bis trifluoroacetic acid salt, 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bis trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide, 5-Cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide trifluoroacetic acid salt, 4-Cyano-1H-imidazole-2-carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt, 5-Cyano-1H-imidazole-2-carboxylic acid {4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide trifluoroacetic acid salt, and 5-Cyano-1H-imidazole-2-carboxylic acid [6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 18. A compound selected from the group consisting of: 4-Cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide, 4-Cyano-1H-imidazole-2-carboxylic acid [1′-(2-dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt, and 4-Cyano-1H-imidazole-2-carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
 19. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 20. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of claim
 1. 21. A dosage form according to claim 20 adapted for parenteral or oral administration.
 22. A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of claim
 1. 23. A method according to claim 22, wherein the protein tyrosine kinase is c-fms.
 24. A method of treating inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim
 1. 25. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim
 1. 26. A method of treating cardiovascular disease in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim
 1. 27. A method of treating diseases with an inflammatory component including glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia or Alzheimer's dementia in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim
 1. 28. A method of treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim
 1. 29. A method of treating osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim
 1. 30. A method of treating and of preventing metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim
 1. 31. A method of treating autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrom, multiple sclerosis, or uveitis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim
 1. 